REVIEW ARTICLE
Pharmacokinetics and Pharmacodynamics in Clinical
Use of Scopolamine
Ulf D. Renner, Reinhard Oertel, and Wilhelm Kirch
Abstract: The alkaloid L-(2)-scopolamine [L-(2)-hyoscine] com-
petitively inhibits muscarinic receptors for acetylcholine and acts as
a nonselective muscarinic antagonist, producing both peripheral anti-
muscarinic properties and central sedative, antiemetic, and amnestic
effects. The parasympatholytic scopolamine, structurally very similar
to atropine (racemate of hyoscyamine), is used in conditions requiring
decreased parasympathetic activity, primarily for its effect on the eye,
gastrointestinal tract, heart, and salivary and bronchial secretion glands,
and in special circumstances for a CNS action. Therefore, scopolamine
is most suitable for premedication before anesthesia and for antie-
metic effects. This alkaloid is the most effective single agent to prevent
motion sickness. Scopolamine was the first drug to be made commer-
cially available in a transdermal therapeutic system (TTS-patch) de-
livering alkaloid. Recently, pharmacokinetic data on scopolamine in
different biozlogic matrices were obtained most efficiently using liq-
uid chromatographictandem mass spectrometric (LC-MS/MS) or
gas chromatography online coupled to mass spectrometry.
Pharmacokinetic parameters are dependent on the dosage form
(oral dose, tablets; parenteral application; IV infusion; SC and IM in-
jection). Scopolamine has a limited bioavailability if orally admin-
istered. The maximum drug concentration occurs approximately
0.5 hours after oral administration. Because only 2.6% of nonmet-
abolized L-(2)-scopolamine is excreted in urine, a first-pass metab-
olism is suggested to occur after oral administration of scopolamine.
Because of its short half-life in plasma and dose-dependent adverse
effects (in particular hallucinations and the less serious reactions, eg,
vertigo, dry mouth, drowsiness), the clinical use of scopolamine
administered orally or parenterally is limited. To minimize the relatively
high incidence of side effects, the transdermal dosage form has been
developed. The commercially available TTS-patch contains a 1.5-mg
drug reservoir and a priming dose (140 mg) to reach the steady-state
concentration of scopolamine quickly. The patch releases 0.5 mg
alkaloid over a period of 3 days (releasing rate 5 mg/h). Following the
transdermal application of scopolamine, the plasma concentrations of
the drug indicate major interindividual variations. Peak plasma
concentrations (Cmax) of approximately 100 pg/mL (range 11240 pg/
mL) of the alkaloid are reached after about 8 hours and achieve steady
state. During a period of 72 hours the plaster releases scopolamine, so
constantly high plasma levels (concentration range 56245 pg/mL) are
obtained, followed by a plateau of urinary scopolamine excretion.
Received for publication November 1, 2004; accepted March 1, 2005.
From the Institute of Clinical Pharmacology, Medical Faculty Carl Gustav
Carus, Technical University of Dresden, Dresden, Germany.
Reprints: Dr. Reinhard Oertel, Institute of Clinical Pharmacology, Medical
Faculty Carl Gustav Carus, Technical University of Dresden, Fiedlerstrasse
27, D-01307 Dresden, Germany (e-mail: reioer@rcs.urz.tu-dresden.de).
Copyright 2005 by Lippincott Williams & Wilkins
Ther Drug Monit  Volume 27, Number 5, October 2005
Although scopolamine has been used in clinical practice for many
years, data concerning its metabolism and the renal excretion in man are
limited. After incubation with b-glucuronidase and sulfatase, the
recovery of scopolamine in human urine increased from 3% to
approximately 30% of the drug dose (intravenously administered).
According to these results from enzymatic hydrolysis of scopolamine
metabolites, the glucuronide conjugation of scopolamine could be
the relevant pathway in healthy volunteers. However, scopolamine
metabolism in man has not been verified stringently. An elucidation of
the chemical structures of the metabolites extracted from human urine is
still lacking.
Scopolamine has been shown to undergo an oxidative demethylation
during incubation with CYP3A (cytochrome P-450 subfamily). To
inhibit the CYP3A located in the intestinal mucosa, components of
grapefruit juice are very suitable. When scopolamine was administered
together with 150 mL grapefruit juice, the alkaloid concentrations con-
tinued to increase, resulting in an evident prolongation of tmax (59.5 6
25.0 minutes; P , 0.001). The AUC024h values of scopolamine were
higher during the grapefruit juice period. They reached approximately
142% of the values associated with the control group (P , 0.005).
Consequently, the related absolute bioavailabilities (range 6% to 37%)
were significantly higher than the corresponding values of the drug orally
administered together with water (range 3% to 27%).
The effect of the alkaloid on quantitative electroencephalogram
(qEEG) and cognitive performance correlated with pharmacokinetics was
shown in studies with healthy volunteers. From pharmacokinetic
pharmacodynamic modeling techniques, a direct correlation between
serum concentrations of scopolamine and changes in total power in
a-frequency band (EEG) in healthy volunteers was provided.
The alkaloid readily crosses the placenta. Therefore, scopolamine
should be administered to pregnant women only under observation. The
drug is compatible with nursing and is considered to be nonteratogenic.
In conclusion, scopolamine is used for premedication in anesthesia
and for the prevention of nausea and vomiting associated with motion
sickness. Pharmacokinetics and pharmacodynamics of scopolamine
depend on the dosage form. Effects on different cognitive functions have
been extensively documented.
Key Words: scopolamine, pharmacokinetics, pharmacodynamics
(Ther Drug Monit 2005;27:655665)
CHEMISTRY AND DOSAGE FORMS
OF SCOPOLAMINE
T
he parasympathicolytic drugs constitute a large class of
anticholinergic agents and can be divided into 2 sub-
classes: (1) natural parasympathicolytics (eg, scopolamine,
atropine) and (2) (semi)synthetic parasympathicolytic agents.
655
Renner et al
The latter subclass consists of quaternary ammonium com-
pounds with ganglioplegic effects (eg, N-butyl-scopolamine)
and substances with additional myogenous spasmolytic
properties (eg, denaverine). The quaternary ammonium moiety
in synthetic parasympatholytic drugs minimize the side effects
on the central nervous system (CNS) because the polar
structures decrease their lipid solubility and prevent crossing
the bloodcerebrospinal fluid barrier.
L-(2)-Scopolamine (synonym: L-(2)-hyoscine) is found
in various Solanaceae, eg, Scopola carniolica, Hyoscyamus
niger, and Datura stramonium. The structure of the tertiary
amine L-(2)-scopolamine (tropic acid ester with scopine;
MW = 303.4; Fig. 1) is very similar to that of atropine
[(6)-hyoscyamine = racemate of hyoscyamine].
The structures of both substances have 1 asymmetric
carbon atom (chiral center) localized in the tropic acid com-
ponent [S-(2)-tropate]. Derived from the tropine substructure
in the atropine compound, the scopine moiety differs only in an
epoxy function, bridged over the C-C bond (position C-6b and
C-7b) of the 1aH,5aH-tropan-3a-ol (tropine).
Scopolamine has a weak basic character (pKa = 7.6) and
a good lipid solubility expressed by a partition coefficient of
1.2 (n-octanol:buffer pH 7.4).
The drug reacts as a nonselective muscarinic antagonist
with both peripheral antimuscarinic properties and central
sedative, antiemetic, and amnestic effects.1
The atropine-like drugs are used in conditions requiring
decreased parasympathetic activity, primarily for their effect
on the eye, gastrointestinal tract, heart, secretions, and in
special circumstances for a CNS action. Scopolamine is more
potent than atropine on the eye, salivary and bronchial secre-
tion glands, and on CNS. Therefore, this drug is most suitable
for use for preoperative sedation as an injection and for its
antiemetic effect as subcutaneous dosage.
Scopolamine was the first drug to be made commercially
available as a transdermal therapeutic system (TTS) delivering
drug (Scopoderm TTS patches, Novartis).2 Because the
postauricular area is the most permeable skin site, a trans-
dermal scopolamine patch is placed on a hairless area behind
the ear for motion sickness and prevention of postoperative
nausea and vomiting.
For refraction, ophthalmic scopolamine (1 or 2 drops) is
applied topically to the eye 1 hour before refraction; for uveitis,
1 or 2 drops are applied up to 4 times daily.
FIGURE 1. Structure of L-(2)-scopolamine (L-(2)-hyoscine), atropine (hyoscyamine), and N-butyl-L-(2)-scopolamine; * =
chiral center.
656
Ther Drug Monit  Volume 27, Number 5, October 2005
Scopolamine is available in infusion solutions with 0.3,
0.5, or 1.0 mg/mL scopolamine hydrobromide
3H2O in a
transdermal patch containing a reservoir of 1.5 mg scopol-
amine (mean release 1.0 mg/72 hours) and in eye drops with
2.1 mg scopolamine borate dissolved in 1 g solution. A nasal
administration of scopolamine was tested using an aerosol
spray releasing 0.1% or 0.2% scopolamine hydrobromide.3,4
ANALYTIC METHODS
First data1,59 about pharmacokinetics (PK) of scopol-
amine were obtained using a stereospecific enzyme immuno-
assay [sensitivity to L-(2)-hyoscine, 20 ng/L] or a radio-
receptor assay (RRA) for the hyoscine racemate based on the
competition between the alkaloid and a radiolabeled ligand for
binding to a certain receptor.
To remove compounds interfering with scopolamine
detection by a radioreceptor assay, high-performance liquid
chromatography (HPLC) was used to separate the analyte.3
Several HPLC methods were developed for the analysis of
scopolamine in biologic matrices (eg, plasma, urine, plants).1012
Capillary zone electrophoresis (CZE) coupled to UV
detection and interfaced with electrospray ionization (ESI)
mass spectrometry is described for the analysis of scopolamine
in plants.13
In recent years both liquid chromatographytandem
mass spectrometry (LC-MS/MS)10,14 and gas chromatography
online coupled to mass spectrometry (GC-MS) have been used
to determine concentrations of scopolamine in different bio-
logic matrices (eg, plasma, serum).1520
For GC-MS/MS methods for generating pharmacoki-
netic data on scopolamine in 1 mL serum19 or 4 mL plasma,16
respectively, extensive sample preparation consisted of
a liquidliquid extraction, and a precolumn derivatization is
necessary to achieve a sensitivity of 50 ng/L.
The liquid chromatographytandem mass spectrometry
(LC-MS/MS) with an automated solid-phase extraction (SPE)
sample preparation is the most qualified method to determine
scopolamine in serum samples of patients, requiring smaller
serum volumes and enabling a lower limit of quantification.
The chromatographic separation is performed on a
RP18e column with a mobile phase gradient. High sensitivity
is provided by detecting both mass transitions between m/z 304
and m/z 138 and between m/z 304 and m/z 156 in the tandem
q 2005 Lippincott Williams & Wilkins
Ther Drug Monit  Volume 27, Number 5, October 2005
mass spectrometer. The limit of quantification of scopolamine,
ie, a coefficient of variation ,20% for 6 repeated measure-
ments, is 20 ng/L.10
PHARMACOKINETICS
Administration and Plasma Concentrations
The pharmacokinetic parameters depend on the dosage
form (Table 1). The oral dose (tablets), parenteral injection
(intravenous, subcutaneous, or intramuscular), and the trans-
dermal form are different administration modes well established
for scopolamine.
Following oral administration the bioavailability of
scopolamine is limited. The pharmacokinetic profile com-
prises levels returning close to baseline 5 to 6 hours after dose.
The pharmacokinetics of 0.5 mg scopolamine orally admin-
istered together with 150 mL water to female and male healthy
volunteers were (geometric mean 6 geometric SD) tmax = 23.5 6
8.2 minutes, Cmax = 0.54 6 0.10 ng/mL, t = 63.7 6 1.3
minutes, AUC024h = 50.77 6 1.76 ng
min/mL, and F = 13 6
1% (F = AUCoral/AUCIV; absolute bioavailability).15
The pharmacokinetic parameters of scopolamine (after
IV infusion of 0.5 mg over period of 15 minutes) were shown
to be as follows (geometric mean 6 geometric SD): CL =
81.2 6 1.55 L/h, Vd = 141.3 6 1.6 l, t = 68.7 6 1.0 minutes,
Cmax = 5.00 6 0.43 ng/mL, and AUC024h = 369.4 6 2.2
ng
min/mL (Fig. 2). The Cmax value in the male subjects was
significantly higher compared with the value in the female
subjects (6.61 6 0.63 ng/mL vs 3.93 6 0.04 ng/mL; P =
0.007). Relating to the other parameters, there were no dif-
ferences in sex. The pharmacokinetic parameters obtained
after oral and intravenous administration were calculated
according to a noncompartment model.15
After subcutaneous administration of 0.4, 0.6, or 0.8 mg
scopolamine to male healthy volunteers, Cmax increased from
3.27 ng/mL to 18.81 ng/mL, and AUC08h from 158.2 to 455.6
ng
min/mL, dependent on dose. In contrast, tmax ranged
between 11.4 and 17.8 minutes, t between 3.3 and 3.8 hours,
and CL between 0.14 and 0.17 L/h independent of the alkaloid
dose. A large interindividual variation of the serum concen-
trations of scopolamine was found.17
Scopolamine is rapidly absorbed from muscle, eg,
deltoid muscle. Following intramuscular injection of scopol-
amine (0.5 mg), the corresponding pharmacokinetic values
TABLE 1. The Most Important Pharmaco Kinetic Data
Application IV Oral
Dose (mg) 0.5 0.5
Cmax (ng/mL) 5.00 6 0.43 0.54 6 0.10
tmax (min) 5.0 23.5 6 8.2
AUC
(ng*min/mL) 369.4 6 2.2 50.8 6 1.76
t1/2 (min) 68.7 6 1.0 63.7 6 1.3
F (%) 100 13 6 1
ND, no data.
q 2005 Lippincott Williams & Wilkins
Scopolamine Pharmacokinetics
FIGURE 2. Area under scopolamine concentration in serum
versustime (AUC) curve following intravenous infusion of

0.5 mg scopolamine in 7 healthy male ( ) and 7 healthy
female volunteers (s). The solid bar represents infusion dura-
tion. From Ebert et al15 with permission.
were Cmax = 0.96 6 0.17 ng/mL (mean of 10 individual
maximum drug concentrations 6 SD), tmax = 18.5 6 4.7
minutes (mean 6 SD), AUC06h = 81.27 6 11.21 ng
min/mL
(mean 6 SD), tlag = 3.4 6 1.40 minutes (lag time after
IM injection; mean 6 SD), and tb = 69.1 6 8.00 minutes
(mean 6 SD).20
Because of its short half-life in plasma and dose-
dependent adverse effects (in particular hallucinations and the
less serious reactions, eg, vertigo, dry mouth, drowsiness), the
clinical use of scopolamine administered orally or parenterally
(bolus therapy) is limited. An intravenous infusion study
established the relationship between adverse effects of the
drug and the increasing urinary excretion of scopolamine.21,22
To minimize the relatively high incidence of side effects,
the transdermal dosage form was developed. The transdermal
delivery system for scopolamine was introduced in 1981. The
commercially available small round TTS-patch (4 layers;
thickness 0.2 mm; size 2.5 cm2) contains a 1.5-mg drug
reservoir and a priming dose (140 mg) to bring plasma con-
centrations of scopolamine to steady state. The patch releases
0.5 mg alkaloid over a period of 3 days (releasing rate 5 mg/h).
Relative to the release and skin permeation of scopol-
amine in vitro, the urinary drug excretion in vivo approaches
a 0.1-fold rate of the alkaloid release in vitro approximately 4
hours after application of the TTS patch, assuming a recovery
of only 10% unchanged drug in urine. Thus, scopolamine is
constantly excreted in urine over a period of many hours.23,24
SC IM IN
0.4 0.5 0.4
3.27 0.96 6 0.17 1.68 6 0.23
14.6 18.5 6 4.7 2.2 6 3
158.2 81.3 6 11.2 167 6 20
213 69.1 6 8.0 ND
ND ND 83 6 10
657
Renner et al Ther Drug Monit  Volume 27, Number 5, October 2005

Following the transdermal application of a scopolamine
via TTS-patch, the plasma scopolamine concentrations com-
bined with the urinary excretion of the drug were analyzed in
patients and children.2540 The plasma concentrations of the
drug indicated major interindividual variations. Peak plasma
concentrations (Cmax) of approximately 100 pg/mL (range 11
240 pg/mL) of the alkaloid were achieved after about 8 hours
and reached steady state. Over a period of 72 hours the plaster
was releasing scopolamine, constant high plasma levels (range
of the peak values: 56245 pg/mL) were obtained, followed by
a plateau of urinary scopolamine excretion.
For comparison to the oral and IV administration, the
bioavailability of scopolamine intranasally (IN) administered
was analyzed in healthy nonsmoking male volunteers.3 The
subjects received a 0.4-mg dose of scopolamine hydrobromide
intranasally on 3 occasions, with at least 2 weeks separating
the doses. The absorption after IN drug application was rapid,
and the pharmacokinetic parameters (mean 6 SD) were Cmax =
1.68 6 0.23 ng/mL, tmax = 22.2 6 3 minutes, AUC024h =
166.8 6 19.8 ng
min/mL, and FIN = 83 6 10%. The absolute
bioavailability FIN was found to significantly greater than that
of FPO (P , 0.05). Time to reach maximum effect was 1.05
hours after IN dosage.3
After ocular administration, scopolamine is rapidly,
efficiently, and systemically absorbed. The systemic absorp-
tion of the alkaloid eye drops (40 mL 0.25% scopolamine
hydrobromide ophthalmic solution) given unilaterally to the
lower cul-de-sac of the operated or affected eye was quantified
in 8 patients.5 The 2 groups, scopolamine and control placebo
group, did not differ with respect to sex distribution, age,
weight, or height. The plasma concentration (mean 6 SD) of
scopolamine was 400 6 50 pg/mL after 3 minutes and was
decreased to 120 6 20 pg/mL at 90 minutes. Cmax (mean 6
SD) was 550 6 60 pg/mL and was reached within 15 minutes
(tmax) in all but 2 patients. In these 2 subjects the peak plasma
concentration of scopolamine was at 60 minutes with a value
of 340 pg/mL, and at 30 minutes with a peak concentration of
280 pg/mL, respectively. Compared with the placebo group,
ocular scopolamine did not affect the blood pressure in
patients. Before administration the salivary secretion was
0.319 6 0.05 g in the scopolamine and 0.416 6 0.147 g in the
placebo group. Thirty minutes after eye drop application, the
secretion was reduced by 0.012 6 0.040 g in the scopolamine
and increased by 0.074 6 0.048 g (P = 0.19) in the placebo
group from the pretreatment value.
Scopolamine is a relatively nonpolar, tertiary amino
compound and should be well absorbed from the gastroin-
testinal tract. However, one of the pharmacological effects of
this drug is the suppression of intestinal motility and gastric
secretion. Both effects may influence the absorption after oral
administration and limit oral bioavailability of scopol-
amine.42 Only 2.6% of the drug is excreted in urine in
a pharmacologically active form.43 Based on this fact, a first-
pass metabolism is suggested to occur after oral administra-
tion of scopolamine.
Concerning the limited data about metabolism of
scopolamine in man and, on the other hand, the potential
variety of scopolamine metabolites, the metabolic pathways of
scopolamine analyzed in animal studies are to be described
more in detail.
In studies with scopolamine administered subcutane-
ously and intraperitoneally, respectively, different metabolites
were identified chemically in the urine of several mam-
mals.44,45 Total unchanged scopolamine and the metabolites
excreted in 24-hour urine of mammals varies in diverse animal
species both qualitatively and quantitatively (range 29% to
.80% of the administered dose). Various metabolic pathways
are shown in Figure 5. Following the administration and
metabolism of L-(2)-[9-14C]scopolamine, the radioactivity of
the N-methyl group of the scopine component was expired
as 14CO2 by mammals. The same result was obtained after
injection of L-(2)-[9-14C]scopolamine-9#-glucuronide into
these mammalian species. With expiring 14CO2, this

Protein Binding
The plasma protein binding of drugs has been shown to
have significant effects on numerous aspects of clinical
pharmacokinetics (PK) and pharmacodynamics (PD). Hitherto
existing measurements of the protein binding of scopolamine
are in rats and showed a low value of 30 6 10%.41

Metabolism and Excretion

Although the drug scopolamine has been used in clinical
practice for many years, little data concerning its metabolism
and renal excretion in healthy volunteers and patients have FIGURE 3. Changes in subjective alertness after scopolamine
been published up to now. (SC). From Ebert et al17 with permission.

658 q 2005 Lippincott Williams & Wilkins

Ther Drug Monit  Volume 27, Number 5, October 2005
scopolamine conjugate was also metabolized to its corre-
sponding nor-compound.44
The different apo compounds of the scopolamine,
L-(2)-aposcopolamine and L-(2)-aponorscopolamine, were
shown not to be artifacts derived during the extraction of the
drug and its conjugates from the biologic matrix. L-(2)-
Aposcopolamine, a gem-substituted styrene derivative, was
proved to be generated (dehydratation reaction) via the
scopolamine-O-sulfate ester, which was produced by an en-
zymatic (sulfotransferase) reaction.46
Without any structure elucidation of the educts of
the following enzymatic reaction, a mixture of enzymes,
b-glucuronidase and b-glucuronide sulfatase (eg, glusulaseTM),
was used in vitro for hydrolysis of the conjugated scopolamine
metabolites in mammalian urine.45 Accordingly, it is just pos-
sible that the sulfate conjugation might have a role in the
metabolism of the alkaloid. However, the fact that saccharo-1,4-
lactone, an inhibitor of b-glucuronidase, completely inhibited
hydrolysis of the conjugates with b-glucuronidase/sulfatase
preparation indicated no or minimal excretion of sulfate con-
jugates as in vivo metabolites of scopolamine in mammals.45
In addition, there was no racemization of the scopol-
amine itself or any optically active metabolites in any animal
species during passage through the organism. This result was
obtained indirectly using the stereospecific (2)-hyoscyamine
acylhydrolase enzyme for the analysis of the optical activity of
scopolamine and its metabolites. Under the catalysis of this
enzyme, an ester cleavage in the L-(2)-scopolamine structure
takes place, resulting in scopine and L-(2)-tropic acid.
The (2)-hyoscyamine acylhydrolase is contained in
organ homogenates and body fluids of several mammals,
especially in rabbit serum, but in matrices of humans the
enzyme is hardly traceable.44
The amounts of metabolites excreted in mammals are
highly species specific, and their relationship is largely inde-
pendent of the administered dose. The pharmacological ac-
tivities of the identified metabolites have not been analyzed
so far.
Little data about the metabolism in healthy volunteers has
been published, indicating the glucuronide or sulfate conjugation
as the significant metabolic pathway of L-(2)-scopolamine.
Following an incubation with b-glucuronidase/sulfatase, the
amount of scopolamine in human urine increased from 3%
up to approximately 30% of the drug dose (intravenously
administered).15,47 However, an analysis stringently verifying
the metabolism in man is still lacking. Compared with the
metabolism in mammals, it is also not evident so far how many
different glucuronide conjugates of scopolamine and its
derivatives (apo- and nor-compounds) are produced in man.
Therefore, following a complete chromatographic analysis, the
chemical structures of the metabolites isolated from human
urine still have to be elucidated. Scopolamine metabolites
excreted in urine of mammals or man are summarized in
Figure 5.
Another possible route to eliminate metabolites is excre-
tion into feces. Verifying the excretion of the drug via the
intestine, there are only few data. In studies describing scopo-
lamine metabolism in mice, small amounts of the unchanged
L-(2)-scopolamine and the scopolamine-9#-glucuronide were
q 2005 Lippincott Williams & Wilkins
Scopolamine Pharmacokinetics
found in feces combined with intestinal contents.44 However,
neither the drug itself nor any of its metabolites were detected
in feces of rats.45 Results of analogous investigations in man
have not been published.
Factors Affecting Scopolamine
Pharmacokinetics
In vitro studies on the interaction of scopolamine with
microsomal cytochrome P-450 (CYP) have shown an
oxidative demethylation of the drug during incubation with
CYP.48 The demethylation is related to the CYP3A sub-
family.49 This result is confirmed by the in vivo investigations
using L-(2)-[9-14C]scopolamine (see above).
To inhibit the CYP3A enzymes efficiently, components
of grapefruit juice are very suitable.50,51 Here, the predominant
in vivo mechanism was suggested to be located primarily in
the mucosa of the small intestine52 because grapefruit juice has
no essential effect on drug metabolism in the liver.53
The CYP3A activity in hepatic and intestinal micro-
somes has been demonstrated to be greater in women than in
men.54,55 In a clinical study the influence of grapefruit juice on
scopolamine pharmacokinetics in healthy male and female
volunteers was shown.15 When scopolamine was administered
together with 150 mL grapefruit juice scopolamine concen-
trations continued to increase for a longer period, resulting
in an evident prolongation of tmax (59.5 6 25.0 minutes;
P , 0.001). The AUC024h values of scopolamine were higher
during the grapefruit juice period. They reached approximately
142% of the values associated with the control group (water
period; P . 0.005). Consequently, the corresponding absolute
bioavailabilities of scopolamine (range 6% to 37%) were
significantly higher than the values after oral administration
together with water (range 3% to 27%).
Cmax of scopolamine administered intravenously and
determined in male subjects was significantly higher compared
with the corresponding Cmax in female subjects. But after oral
administration of scopolamine together with grapefruit juice or
water, no differences in the pharmacokinetic parameters of the
drug were found between male and female subjects. Appro-
ximately 30% of the dose administered was excreted in urine
as unchanged drug or as glucuronide conjugate independent of
the sex and of the route of administration (infusion, per os
administration with water or with grapefruit juice). The
elimination was not significantly affected.15
With regard to transdermal delivery of scopolamine, the
skin temperature of the patients is not decisive. However,
permeation across human skin in vitro is significantly
intensified by increasing the scopolamine concentration or
raising the pH of the diffusing drug solution.23,56
In the same manner the nasal absorption of scopolamine
in human subjects is influenced by pH value and dosage. The
average AUC value was found to be significantly higher for pH
9.0 formulation as compared with those of pH 4.0 and pH 7.0,
respectively. Both the Cmax and AUC values were almost doubled
with doubling the dose. The average tmax values decreased
linearly with a decrease in formulation pH at both doses.14
Pharmacokinetics of scopolamine is able to be influenced
by oral contraceptives. Depending on the dose administered,
659
Renner et al
FIGURE 4. Representative example of the concentrationEEG
effect relationship (a power) in occipital electrode positions
after intravenous infusion of 0.5 mg scopolamine hydro-
bromide in a healthy volunteer. Solid line represents the
optimal fit of the actual data points. Cp(t) = predicted serum
concentration of scopolamine at time t. From Ebert et al20 with
permission.
FIGURE 5. Metabolic pathways of L-(2)-scopolamine.
660
Ther Drug Monit  Volume 27, Number 5, October 2005
the contraceptives may inhibit the metabolism of scopolamine,
decrease plasma albumin concentrations by 3% to 12%, and
may change the clearance.5759
PHARMACODYNAMICS AND ADVERSE
EFFECTS OF SCOPOLAMINE
After IV infusion, scopolamine significantly decreased
subjective alertness in both male and female subjects
compared with baseline (P , 0.05) without any differences
by sex.15,6062 Time-dependent disturbances occurred maxi-
mally 0.52 hours after starting IV infusion of scopolamine in
both male and female volunteers.
In addition a slight decrease in subject alertness was
observed after oral administration of scopolamine with water
or grapefruit juice compared with baseline (P , 0.05) in both
male and female subjects without any differences by sex.15
q 2005 Lippincott Williams & Wilkins
Ther Drug Monit  Volume 27, Number 5, October 2005
Twenty-four hours after drug administration, the sub-
jective state was not significantly different from baseline value
in either male or female subjects.15
Scopolamine orally administered shows an effectiveness
in preventing motion sickness within 0.5 hours for a period of
6 hours. The transdermal administration of the same drug is
effective over a period of 72 hours. However, by this route the
effect is not achieved until 6 to 8 hours postapplication.9On the
other hand, simultaneously with the stimulation or inhibition,
respectively, of other neurotransmitters (eg, serotonergic neu-
rotransmission63 and the dopaminergic system64), the cholin-
ergic system is involved in the storage and retrieval of
information during new learning. The blockade of central
muscarinic receptors induces a memory deficit in young sub-
jects that is similar to that occurring in elderly subjects.60,62,65
Age-related changes in the central cholinergic system are
reflected in a decreased functional activity of cholinoreceptive
neurons. In addition, studies in patients with Alzheimer dis-
ease have shown a severe loss of neurons in the nucleus basalis
of Meynert.66 The decrease in cortical choline acetyltransfer-
ase found in Alzheimer patients is suggested to reflect a
specific loss of cholinergic input to the cortex65 because the
nucleus basalis of Meynert is believed to provide the primary
cholinergic input to the cortical mantle.67 It is postulated that
postsynaptic muscarinic receptors are permanently destroyed
or inactivated in dementia of the Alzheimer type.68 In stud-
ies of electroencephalogram (EEG) changes and drug effects
on different cognitive functions, scopolamine is commonly
used as a pharmacological model substance based on the
cholinergic hypothesis of memory loss in senile dementia of
the Alzheimer type. However, the scopolamine model is
insufficient to indicate the full range of memory deficits found
in patients with Alzheimer disease.69
The effects of intravenously,20 intramuscularly,20,61 and
subcutaneously17 administered scopolamine on quantitative
EEG (qEEG) and cognitive performance related to pharma-
cokinetic parameters were demonstrated in studies with
healthy volunteers. Scopolamine produced a dose- and time-
dependent impairment of memory and attention. After admin-
istration of scopolamine (0.40.8 mg SC), the drug generated
a time-dependent increase in d power (1.254.50 Hz) and a
decrease in fast a power (9.7512.50 Hz) on qEEG for more
than 8 hours. The temporary changes in cognitive behavior
evaluated by qEEG and psychometric tests (eg, changes in
choice reaction time) are shown in Figure 3.
Pharmacodynamic measurements after intravenous and
intramuscular scopolamine administration (0.5 mg scopol-
amine hydrobromide over a period of 15 minutes, and 0.5 mg
in the upper right arm, respectively) indicated no interday
variability of the baseline values of EEG. The absolute power
in a band (7.5011.25 Hz) decreased after scopolamine
administration. This effect returned gradually to baseline.
Fifteen minutes after beginning scopolamine infusion,
a significant decrease in absolute a power occurred at frontal,
central, and occipital brain areas compared with placebo. This
effect was persistent up to 180 minutes after drug adminis-
tration (P , 0.05).20
Figure 4 shows the relationship between scopolamine
serum concentrations and EEG effects (a power in occipital
q 2005 Lippincott Williams & Wilkins
Scopolamine Pharmacokinetics
electrode positions) derived for an individual healthy subject
after IV scopolamine administration (PK-PD modeling). No
time delay between serum concentrations and EEG effect was
observed, and the corresponding values were directly corre-
lated to each other by a sigmoid Emax model (Emax is the maximal
drug effect).20
Scopolamine administered in pharmacologically effec-
tive doses generates fatigue, dreamless sleep (reduction in
rapid eye movement, REM), amnesia, vertigo, vestibular de-
pression. In contrast, in patients receiving higher scopolamine
doses, the drug can produce a stimulation of the CNS with
symptoms, eg, excitement, hallucinations, irritability.70
The mechanism of action of the anticholinergic
(antimuscarinic) drug scopolamine is the competitive antag-
onism of acetylcholine at the muscarinic receptors.71 For a
better understanding of the pharmacodynamics and the di-
versity of adverse effects caused by scopolamine, the local
distribution of muscarinic receptors (a family of 5 subtypes,
M1M5, is expressed in man) has to be considered. Each of the
human muscarinic receptor proteins (M1M5) is encoded by
a unique gene, and its corresponding amino acid sequence has
been described.72,73 As found with PCR, receptor subtype
mRNAs of M1 to M5 are expressed in the human brainstem,
cerebellum, and cortex. In contrast, the vestibular ganglia and
the vestibular end organs in humans express only M1, M2, and
M5.74 In consequence of these results and previous electro-
physiological and immunohistochemical analyses, the efferent
cholinergic axosomatic and axodentritic synapses are sug-
gested to have muscarinic components having an effect on
motion sickness.75,76
Based on pharmacological studies with experimental
drugs, eg, pirenzepine, AFDX-116, or methocramine (each a
selective antagonist), 3 subtypes (M1, M2, and M3) of muscari-
nic receptors can be defined.72,77
The receptors have been found to regulate a broad range
of physiological and biochemical activities throughout the
CNS via the activation of guanidine nucleotide binding (G)
proteins. Nevertheless the physiological function of these
receptor subtypes is still poorly defined, but the anatomic
location of the subtypes suggests that the neuronal tissues have
a preponderance of M1 receptors. The subtype M2 is situated
predominantly in the heart, and M3 is the glandular sub-
type.72,73
Similar to atropine, L-(2)-scopolamine is a nonselective
muscarinic antagonist.78 The sensitivity of the subtypes seems
to vary in such a way that the inhibition of salivation (M3
receptors) can be produced with low doses, whereas much
higher doses are needed for heart effects (M2 receptors).79,80
As a result of the mechanism of action described above, the
measured plasma levels of scopolamine do not necessarily
correlate with the pharmacodynamic effects of the drug.
The effects of scopolamine on the cardiovascular system
are complex and dose dependent.40 Low doses of the alkaloid
give rise to a slowing of heart rate, whereas higher doses
produce an increase in heart rate dose-dependently. Follow-
ing the inhibition of the vagal transmission of the sinoatrial
node, tachycardia is produced. Such a biphasic doseresponse
curve is prominent with scopolamine. Intravenously admin-
istered doses up to 2.8 mg/kg body weight (bw) produce only
661
Renner et al
bradycardia. After a dose of more than 8.4 mg/kg bw, a tran-
sient tachycardia is observed, is reversed within 30 minutes,
and is followed by a long-lasting bradycardia.81
Scopolamine produces mydriasis and cycloplegia. Here,
the sphincter muscle of the iris and the ciliary muscle of the
lens are paralyzed.40 Eye functions may be impaired up to 7
12 days when scopolamine is administered locally. After orally
or parenterally administered scopolamine, visual problems are
both slow to develop and slow to reverse.82 In addition, only
a small effect on eye pressure is described after oral or parenteral
scopolamine. This is in contrast to the local administration.
However, in patients with narrow-angle glaucoma, the systemic
application of L-(2)scopolamine may induce a dangerous
increase in eye pressure.40
Scopolamine gives a rise to an inhibition of gastric
salivation and secretion. The drug produces dryness of the
mouth and decreases the tone of the smooth muscle in the
gastrointestinal and urinary tract, leading to a decreased
motility.79
Additionally, the motility of stomach and esophagus is
decreased.
Adverse effects of scopolamine in the respiratory tract
are dryness of the mucous membranes of the nasopharynx,
mouth, bronchi, and bronchioli. Following a relaxation of the
smooth muscles after scopolamine administration, the airway
resistance in the respiratory tract is reduced.
Scopolamine (IV) reduces the sweat gland activity and,
hence, the galvanic skin response.83
The tonus and the amplitude of urethra and bladder
contractions may be decreased after scopolamine application.
Therefore, there is a contraindication to the use of the drug in
patients with obstructive uropathy.40
TOXICITY
Because of the limited information on species differ-
ences in the acute toxicity of scopolamine, it is not clear which
metabolites contribute to the toxicity of the drug. For instance,
in toxicity studies of atropine, the metabolite apoatropine,
a styrene derivative, has been demonstrated to possess more
potent acute toxicity than atropine itself.45,84
If the same relation between aposcopolamine and sco-
polamine obtains, the contribution of the dehydrated metab-
olite to the occurrence of scopolamine toxicity may be most
significant in guinea pig because these mammals have the
highest dehydrating capacity among the species examined.
The alkaloid readily crosses the placenta. Therefore, the
administration of scopolamine in pregnant women should
occur only under clinical observation.85,86 The drug is com-
patible with nursing and is not considered to be teratogenic.87
Scopolamine toxicity has been described in a newborn with
symptoms such as tachycardia, fever, and lethargy.
The signs and symptoms of an anticholinergic intoxi-
cation include somnolence, coma, confusion, agitation, hallu-
cinations, convulsion, visual disturbance, dry flushed skin, dry
mouth, urinary retention, decreased bowel sounds, hyperten-
sion, and supraventricular arrythmias.
A case of Frey syndrome is reported characterized by
gustatory sweating and erythema of the face on mastication
662
Ther Drug Monit  Volume 27, Number 5, October 2005
after injury to the parotid gland.88 LD50 was determined in rats
administered 3800 mg/kg bw subcutaneously.89 Although
many epoxides have been observed to show a highly muta-
genic activity, the parasympatholytic drug scopolamine does
not posses such an activity.90
DOSAGE REGIMEN
Scopolamine is used mainly in the prevention of motion
sickness, in various gastrointestinal disorders, and as premed-
ication before anesthesia.
Commercially available patches applied to the postaur-
icular area contain a scopolamine reservoir of 1.5 mg and
deliver 0.5 mg of the drug over a time period of 3 days.
Therefore, after a priming dose of 140 mg delivered in the first
few hours, the drug is released with a constant rate of 5 mg/h
over the following 3 days. The recommended dose applied to
an adult is a single TTS-patch placed on the postauricular area
at least 46 hours before an antiemetic effect is required. If
a shorter period is required to prevent motion sickness,
a combination of a TTS patch and a 0.3 mg tablet is intended
for administration 1 hour before travel. If there is an insuf-
ficient clinical response, a higher dose (0.6-mg scopolamine
tablet) has to be used. The combination of transdermal and oral
scopolamine is extremely efficient in achieving a fast and
prolonged prophylactic protection against motion sickness.9
TTS-patch is not recommended for administration in
children and should be used with special caution in patients with
pyloric obstruction, intestinal obstruction, impaired liver and
kidney function, and urinary bladder neck obstruction. The
scopolamine patch is contraindicated in patients with plaster
allergy, in patients with glaucoma, and in pregnant women.
The clinical effects of scopolamine in patients un-
dergoing cesarean section under general anesthesia were
determined in a clinical study. Using scopolamine instead of
the routine atropine medication, 3 groups of parturients were
administered the alkaloid intravenously, intramuscularly, or
oropharyngeally (intubated patients). The patients of group 1
(IV injection) were slightly sedated only, without amnesia,
and the dryness of the mouth subjectively was reported to be
only moderate. In contrast, in group 2 (IM injection) and group
3 (oropharyngeal application), all patients were markedly
sedated and had complete amnesia up to 1.52 hours after the
end of the anesthesia. All of them reported a strong dryness of
the mouth. According to these measured pharmacodynamics
a single intravenous dose of 5 mg scopolamine per kg bw is
clinically useful without prominent residual effects, but both
the 10 mg/kg intramuscular and 35 mg/kg oropharyngeal doses
caused too strong adverse effects.91 Male patients scheduled
for minor surgery under spinal anesthesia were studied.
Patients received scopolamine (6 mg/kg bw) plus morphine
(200 mg/kg bw) injected in either deltoid or gluteal muscle.
The sedative effect of the drug combination was prominent and
long lasting in both groups.6
CONCLUSION
Scopolamine is a nonselective muscarinic antagonist.
The mechanism of action of the anticholinergic drug
q 2005 Lippincott Williams & Wilkins
Ther Drug Monit  Volume 27, Number 5, October 2005
scopolamine is the competitive antagonism of acetylcholine at
the muscarinic receptors. As a result of the nonpolar structure
of the native parasympatholytic drug, its good lipid solubility
permits almost complete and rapid gastrointestinal absorption
and crossing of the bloodcerebrospinal fluid barrier. Scopol-
amine shows profound sedative, amnesic, and antiemetic ac-
tions. Because of the large number of adverse effects and
the short duration of action following oral, intravenous, or
intramuscular administration, the clinical use is limited.
Nevertheless, scopolamine is the most effective single agent
to prevent motion sickness. To minimize the relatively high
incidence of adverse effects and to extend the duration of
action, the TTS-patch was developed. In several studies TTS-
patches have been shown to reach protective levels after 68
hours, achieving a steady state. The optimal efficacy is
maintained over a period of 72 hours. In contrast, scopolamine
administered orally or intravenously shows an effectiveness in
preventing motion sickness within 0.5 hours for a period of
only 6 hours. However, its bioavailability is limited after oral
administration. The glucuronide conjugation of scopolamine
could be the relevant pathway in a healthy human. This will be
suggested by the results of the enzymatic hydrolysis of con-
jugated metabolites with b-glucuronidase and sulfatase. How-
ever, scopolamine metabolism in humans is not completely
known, and a complete chromatographic analysis followed by
elucidation of the exact chemical structures of the metabolites
extracted from human urine is still lacking.
Inhibiting the CYP3A enzyme with components of
grapefruit juice influences the pharmacokinetics of scopolamine
to produce evident prolongation of tmax, and the AUC024h
values and consequently the bioavailabilities of scopolamine
were significantly higher.
REFERENCES
1. Ali-Melkkila T, Kanto J, Iisalo E. Pharmacokinetics and related
pharmacodynamics of anticholinergic drugs. Acta Anaesthesiol Scand.
1993;37:633642.
2. Ridout G, Santus GC, Guy RH. Pharmacokinetic considerations in the use
of newer transdermal formulations. Clin Pharmacokinet. 1988;15:114
131.
3. Putcha L, Tietze KJ, Bourne DW, et al. Bioavailability of intra-
nasal scopolamine in normal subjects. J Pharm Sci. 1996;85:899
902.
4. Klocker N, Hanschke W, Toussaint S, et al. Scopolamine nasal spray in
motion sickness: a randomised, controlled, and crossover study for the
comparison of two scopolamine nasal sprays with oral dimenhydrinate
and placebo. Eur J Pharm Sci. 2001;13:227232.
5. Lahdes K, Huupponen R, Kaila T, et al. Systemic absorption of ocular
scopolamine in patients. J Ocul Pharmacol. 1990;6:6166.
6. Kentala E, Scheinin H, Kaila T, et al. Pharmacokinetics and clinical effects
of intramuscular scopolamine plus morphine. A comparison of two
injection sites. Acta Anaesthesiol Scand. 1998;42:323328.
7. Kanto J, Klotz U. Pharmacokinetic implications for the clinical use of
atropine, scopolamine and glycopyrrolate. Acta Anaesthesiol Scand.
1988;32:6978.
8. Aaltonen L, Kanto J, Iisalo E, et al. Comparison of radioreceptor assay and
radioimmunoassay for atropine: pharmacokinetic application. Eur J Clin
Pharmacol. 1984;26:613617.
9. Nachum Z, Shahal B, Shupak A, et al. Scopolamine bioavailability in
combined oral and transdermal delivery. J Pharmacol Exp Ther. 2001;
296:121123.
10. Oertel R, Richter K, Ebert U, et al. Determination of scopolamine in
human serum and microdialysis samples by liquid chromatography
q 2005 Lippincott Williams & Wilkins
Scopolamine Pharmacokinetics
tandem mass spectrometry. J Chromatogr B Biomed Sci Appl. 2001;750:
121128.
11. Whelpton R, Hurst PR, Metcalfe RF, et al. Liquid chromatographic
determination of hyoscine (scopolamine) in urine using solid phase
extraction. Biomed Chromatogr. 1992;6:198204.
12. Auriola S, Martinsen A, Oksman-Caldentey KM, et al. Analysis of tropane
alkaloids with thermospray high-performance liquid chromatography
mass spectrometry. J Chromatogr. 1991;562:737744.
13. Mateus L, Cherkaoui S, Christen P, et al. Capillary electrophoresis-diode
array detectionelectrospray mass spectrometry for the analysis of
selected tropane alkaloids in plant extracts. Electrophoresis. 1999;20:
34023409.
14. Ahmed S, Sileno AP, de Meireles JC, et al. Effects of pH and dose on nasal
absorption of scopolamine hydrobromide in human subjects. Pharm Res.
2000;17:974.
15. Ebert U, Oertel R, Kirch W. Influence of grapefruit juice on scopolamine
pharmacokinetics and pharmacodynamics in healthy male and female
subjects. Int J Clin Pharmacol Ther. 2000;38:523531.
16. Bayne WF, Tao FT, Crisologo N. Submicrogram assay for scopolamine in
plasma and urine. J Pharm Sci. 1975;64:288291.
17. Ebert U, Siepmann M, Oertel R, et al. Pharmacokinetics and
pharmacodynamics of scopolamine after subcutaneous administration.
J Clin Pharmacol. 1998;38:720726.
18. Deutsch J, Soncrant TT, Greig NH, et al. Electron-impact ionization
detection of scopolamine by gas chromatographymass spectrometry in
rat plasma and brain. J Chromatogr. 1990;528:325331.
19. Oertel R, Richter K, Ebert U, et al. Determination of scopolamine in
human serum by gas chromatographyion trap tandem mass spectrometry.
J Chromatogr B Biomed Appl. 1996;682:259264.
20. Ebert U, Grossmann M, Oertel R, et al. Pharmacokinetic-pharmacodynamic
modelling of the electroencephalogram effects of scopolamine in healthy
volunteers. J Clin Pharmacol. 2001;41:5160.
21. Shaw JE, Crammer MP, Gale R. Rate-controlled transdermal therapy
using polymeric membranes. In: Kydonieus AF, Berner B, eds: Transdermal
Delivery of Drugs, Vol. I. Boca Raton, FL: CRC Press, 1987, pp 101
116.
22. Berner B, John VA. Pharmacokinetic characterisation of transdermal
delivery systems. Clin Pharmacokinet. 1994;26:121134.
23. Shaw JE, Chandrasekaran SK, Campbell PS, et al. New procedures for
evaluating cutaneous absorption. In: Drill VA, Lazar P, eds. Cutaneous
Toxicity. Proceedings of the 3rd Conference of the American Medical
Association, 1976. New York: Academic Press, 1977, pp 8394.
24. Shaw JE, Chandrasekaran SK, Taskovich L. Use of percutaneous
absorption for systemic administration of drugs. The Pharmaceutical
Journal. 1975;215:325328.
25. Muir C, Metcalfe R. A comparison of plasma levels of hyoscine after
oral and transdermal administration. J Pharm Biomed Anal. 1983;1:363
367.
26. Ensing K, de Zeeuw RA, Ensing GJ. Pharmacokinetics of free and
glucuronidated scopolamine following transdermal delivery of scopol-
amine in children. [abstract] Acta Pharmacol Toxicol (Copenh). 1986;
59(Suppl. 5):81.
27. Ensing K, int Hout WG, Halma P, et al. Development and application of
a radioreceptor assay for scopolamine. Arzneimittelforschung. 1988;38:
106111.
28. Bosman IJ, Douma WR, Ensing K, et al. A semi-automated solid-phase
extraction and radioreceptor assay for the analysis of scopolamine in urine
and plasma. Eur J Pharm Sci. 1997;5:315325.
29. Schmitt LG, Shaw JE, Carpenter PF, et al. Comparison of transdermal and
intravenous administration of scopolamine. [abstract] Clin Pharmacol
Ther. 1981;29:282.
30. Chandrasekaran SK, Bayne W, Shaw JE. Pharmacokinetics of drug
permeation through human skin. J Pharm Sci. 1978;67:13701374.
31. Graybiel A, Knepton J, Shaw J. Prevention of experimental motion
sickness by scopolamine absorbed through the skin. Aviat Space Environ
Med. 1976;47:10961100.
32. Pyykko I, Schalen L, Jantti V. Transdermally administered scopolamine
vs. dimenhydrinate. I. Effect on nausea and vertigo in experimentally
induced motion sickness. Acta Otolaryngol. 1985;99:588596.
33. Homick JL, Kohl RL, Reschke MF, et al. Transdermal scopolamine in the
prevention of motion sickness: evaluation of the time course of efficacy.
Aviat Space Environ Med. 1983;54:9941000.
663
Renner et al
34. Parrott AC, Jones R. Effects of transdermal scopolamine upon
psychological test performance at sea. Eur J Clin Pharmacol. 1985;28:
419423.
35. Graybiel A, Cramer DB, Wood CD. Experimental motion sickness:
efficacy of transdermal scopolamine plus ephedrine. Aviat Space Environ
Med. 1981;52:337339.
36. Doweck I, Dachir S, Spitzer O, et al. Rate of absorption of scopolamine
after application of Scopoderm-TTS. [abstract] Aviat Space Environ Med.
1995;66:467.
37. Doweck I, Nachum Z, Dachir S, et al. Enhancement of transdermal
scopolamine absorption using sonophoresis [abstract]. In: Program and
Abstracts, 44th International Congress of Aviation and Space Medicine,
Jerusalem, Israel, 1996:p 18.
38. Cintron NM, Chen YM. A sensitive radioreceptor assay for determining
scopolamine concentrations in plasma and urine. J Pharm Sci. 1987;6:
328332.
39. Parrott AC. Transdermal scopolamine: a review of its effects upon motion
sickness, psychological performance, and physiological functioning. Aviat
Space Environ Med. 1989;60:19.
40. Clissold SP, Heel RC. Transdermal hyoscine (scopolamine). A pre-
liminary review of its pharmacodynamic properties and therapeutic
efficacy. Drugs. 1985;29:189207.
41. Nakashima E, Ishizaki J, Takeda M, et al. Pharmacokinetics of
anticholinergic drugs and brain muscarinic receptor alterations in
streptozotocin diabetic rats. Biopharm Drug Dispos. 1993;14:673
684.
42. Putcha L, Cintron NM, Tsui J, et al. Pharmacokinetics and oral
bioavailability of scopolamine in normal subjects. Pharm Res. 1989;6:
481485.
43. Kanto J, Kentala E, Kaila T, et al. Pharmacokinetics of scopolamine
during caesarean section relationship between serum concentration and
effect. Acta Anaesthesiol Scand. 1989;33:482486.
44. Werner G, Schmidt KH. [Studies on the metabolism of tropane alkaloids.
8. Chemical analysis of (2)-scopolamine metabolism in several mammals]
Hoppe Seylers Z Physiol Chem. 1968;349:741752.
45. Wada S, Yoshimitsu T, Koga N, et al. Metabolism in vivo of the tropane
alkaloid, scopolamine, in several mammalian species. Xenobiotica. 1991;
21:12891300.
46. Wada S, Shimizudani T, Yamada H, et al. Sulphotransferase-dependent
dehydration of atropine and scopolamine in guinea pig. Xenobiotica.
1994;24:853861.
47. Kentala E, Kaila T, Ali-Melkkila T, et al. beta-Glucuronide and sulphate
conjugation of scopolamine and glycopyrrolate. Int J Clin Pharmacol
Ther Toxicol. 1990;28:487489.
48. Peeples A, Dalvi RR. Toxic alkaloids and their interaction with
microsomal cytochrome P-450 in vitro. J Appl Toxicol. 1982;2:300
302.
49. Ristau O, Wagnerova DM, Rein H, et al. Demethylation of tertiary amines
by a reconstituted cytochrome P-450 enzyme system: kinetics of oxygen
consumption and hydrogenperoxide formation. J Inorg Biochem. 1989;
37:111118.
50. Bailey DG, Arnold JM, Spence JD. Grapefruit juice and drugs. How
significant is the interaction? Clin Pharmacokinet. 1994;26:9198.
51. Fuhr U, Kummert AL. The fate of naringin in humans: A key to
grapefruit juice-drug interactions? Clin Pharmacol Ther. 1995;58:
365373.
52. Kivisto KT, Bookjans G, Fromm MF, et al. Expression of CYP3A4,
CYP3A5 and CYP3A7 in human duodenal tissue. Br J Clin Pharmacol.
1996;42:387389.
53. Fuhr U. Drug interactions with grapefruit juice. Extent, probable
mechanism and clinical relevance. Drug Saf. 1998;18:251272.
54. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the
activity of human hepatic CYP3A. Biochem Pharmacol. 1992;44:275
283.
55. Lown KS, Kolars JC, Thummel KE, et al. Interpatient heterogeneity in
expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction
by the erythromycin breath test. Drug Metab Dispos. 1994;22:947955.
Erratum in: Drug Metab Dispos. 1995;23.
56. Shaw JE, Chandrasekaran SK. Transdermal therapeutic systems. In:
Prescott LF, Nimmo WS, eds. Drug Absorption: The Proceedings of the
International Conference on Drug Absorption; Edinburgh, September,
1979. New York: ADIS Press, 1981:pp 186193.
664
Ther Drug Monit  Volume 27, Number 5, October 2005
57. Juchau MR, Fouts JR. Effects of norethynodrel and progesterone on
hepatic drug-metabolizing enzyme systems. Biochem Pharmacol. 1966;
15:891898.
58. Song CS, Merkatz IR, Rifkind AB, et al. The influence of pregnancy and
oral contraceptive steroids on the concentration of plasma proteins. Am J
Obstet Gynecol. 1970;108:227231.
59. Wilson K. Sex-related differences in drug disposition in man. Clin
Pharmacokinet. 1984;9:189202.
60. Ghoneim MM, Mewaldt SP. Studies on human memory: the interaction of
diazepam, scopolamine, and physostigmine. Psychopharmacology (Berl).
1977;52:16.
61. Sannita WG, Maggi L, Rosadini G. Effects of scopolamine (0.250.75 mg
i.m.) on the quantitative EEG and the neuropsychological status of healthy
volunteers. Neuropsychobiology. 1987;17:199205.
62. Wesnes KA. An investigation of the range of cognitive impairments
induced by scopolamine0.6 mg s.c. Hum Psychopharmacol. 1988;3:
2741.
63. Blokland A. Acetylcholine: a neurotransmitter for learning and memory?
Brain Res Rev. 1996;21:285300.
64. Dunnett SB, Robbins TW. The functional role of the mesotelencephalic
dopamine systems. Biol Rev. 1992;67:491518.
65. Bartus RT, Dean RL, Beer B, et al. The cholinergic hypothesis of geriatric
memory dysfunction. Science. 1982;217:408417.
66. Whitehouse PJ, Price DL, Clark AW, et al. Alzheimer disease: evidence
for selective loss of cholinergic neurons in the nucleus basalis. Ann
Neurol. 1981;10:122126.
67. Wenk H, Bigl V, Meyer U. Cholinergic projections from magnocellular
nuclei of the basal forebrain to cortical areas in rats. Brain Res. 1980;2:
295316.
68. Sunderland T, Tariot PN, Cohen RM, et al. Anticholinergic sensitivity in
patients with dementia of the Alzheimer type and age-matched controls:
a dose-response study. Arch Gen Psychiat. 1987;44:418426.
69. Ebert U, Kirch W. Scopolamine model of dementia: electroencephalo-
gram findings and cognitive performance. Eur J Clin Invest. 1998;28:
944949.
70. Brown JH, Taylor P. Muscarinic receptor agonists and antagonists. In:
Hardman JG, Limbird LE, Molinoff PB, et al. eds: Goodman and
Gilmans the Pharmacological Basis of Therapeutics, 9th ed. New York:
McGraw-Hill, 1996:pp 141160.
71. Weiner N. Atropine, scopolamine and related antimuscarinic drugs. In:
Gilman AC, Goodman LS, Rall TW, et al. eds: The Pharmacological
Basis of Therapeutics. New York: Macmillan, 1985:pp 130144.
72. Bonner TI, Buckley NJ, Young AC, et al. Identification of a family of
muscarinic acetylcholine receptor genes. Science. 1987;237:527532.
73. Peralta RG, Winslow JW, Ashkenazi A, et al. Structural basis of
muscarinic acetylcholine receptor subtype diversity. Trends Pharmacol
Sci. 1988;Suppl III:711.
74. Wackym PA, Chen CT, Ishiyama A, et al. Muscarinic acetylcholine
receptor subtype mRNAs in human and rat vestibular periphery. Cell Biol
Int. 1996;20:187192.
75. Gowans J, Matheson A, Darlington CL, et al. The effects of scopolamine
and cyclizine on visualvestibular interaction in humans. J Vestib Res.
2000;10:8792.
76. Gacek RR. Efferent innervation of the labyrinth. Am J Otolaryngol. 1984;
5:206224.
77. Birdsall NJM, Curtis CAM, Eveleigh P, et al. Muscarinic receptor
subtypes and the selectivity of agonists and antagonists. Pharmacology.
1988;37:2231.
78. Wellstein A, Pitschner HF. Complex doseresponse curves of atropine in
man explained by different functions M1- and M2-cholinoceptors.
Naunyn Schmiedebergs Arch Pharmacol. 1988;338:1927.
79. Mirakhur RK, Dundee JW. Gycopyrrolate: pharmacology and clinical use.
Anaesthesia. 1983;38:11951204.
80. Ali-Melkkila T, Kaila T, Kanto J. Glycopyrrolate: pharmacokinetics and
some pharmacodynamic findings. Acta Anaesthesiol Scand. 1989;33:
513517.
81. Gravenstein JS, Thornby JI. Scopolamine on heart rate in man. Clin
Pharmacol Ther. 1968;10:395400.
82. Mirakhur RK. Comparative study of the effects of oral and i.m. atropine
and hyoscine in volunteers. Br J Anaesth. 1978;50:591598.
83. Turner P. Test of autonomic function in assessing centrally-acting drugs.
Br J Clin Pharmacol. 1980;10:9399.
q 2005 Lippincott Williams & Wilkins
Ther Drug Monit  Volume 27, Number 5, October 2005
84. Krantz JC Jr, Forrest JW, Heisse CK. Contribution to the pharmacology of
apoatropine and its methyl bromide. Proc Soc Exp Biol Med. 1954;86:
511512.
85. Ayromlooi J, Tobias M, Berg P. The effects of scopolamine and ancillary
analgesics upon the fetal heart rate recording. J Reprod Med. 1980;25:
323326.
86. Evens RP, Leopold JC. Scopolamine toxicity in a newborn. [letter]
Pediatrics. 1980;66:329330.
87. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in Pregnancy and
Lactation: A Reference Guide to Fetal and Neonatal Risk, 4th ed.
Baltimore: Williams & Wilkins, 1994:pp 777778.
q 2005 Lippincott Williams & Wilkins
Scopolamine Pharmacokinetics
88. Bednarek J, Reid W, Matsumoto T. Freys syndrome. Am J Surg. 1976;
131:592594.
89. Stockhaus K, Wick H. Studies of the toxicity of drugs in subcutaneous,
intragastric and intraduodenal administration in rats. Arch Int Pharma-
codyn Ther. 1969;180:155161.
90. Glatt H, Jung R, Oesch F. Bacterial mutagenicity investigation of
epoxides: drugs, drug metabolites, steroids and pesticides. Mutat Res.
1983;111:99118.
91. Pihlajamaki KK, Kanto JH, Oksman-Caldentey KM. Pharmacokinetics
and clinical effects of scopolamine in caesarean section patients. Acta
Pharmacol Toxicol (Copenh). 1986;59:259262.
665