European Journal of
Eur J Clin Pharmacol (1982) 22:359-365
Pharmacokinetics of Chlorpheniramine After Intravenous
and Oral Administration in Normal Adults
S. M. Huang, 1N. K. Athanikar, 1K. Sridhar, 2Y.C. Huang 1, and W. L. Chiou 1
IDepartment of Pharmacy, College of Pharmacy, University of Illinois, Medical Center, and
2Cook County Hospital, Chicago, Illinois, USA
Summary. Plasma and urinary levels of chlorphenir-
amine (CPM) and its 2 demethylated metabolites
were measured by HPLC after i. v. and oral dosing. In
5 mg (maleate) i.v. bolus studies in 2 subjects, plasma
CPM levels were fitted to triexponential equations
with terminal half-lives (t,/2) of 23 and 22 h and area of
3.6 and 3.21/kg, respectively. Intravenous data pre-
dicted hepatic blood extraction ratios for the 2 sub-
jects to be 0.06 and 0.07, respectively. Absolute bio-
availability from oral solution (10 mg) was 59 and
34%, and from tablets (8 mg) 44 and 25%, respectively,
indicating extensive gut first-pass metabolism. Mean
t,/2 from 7 oral fasting studies in 5 subjects was 28 h
(19-43 h). Mean absorption lag time was 0.7 h
(0.4-1.3 h), and mean peak time was 2.8 h (2-4 h). In
2 subjects, 6 mg solutions were given every 12 h for
9 doses; good correlation between single and multiple
dose kinetics was found. Significant accumulation
was demonstrated in simulation studies with frequent
daily dosing. Estimated accumulation ratios vary
from 4.1 to 9.4 (mean 6.5). The tv, from urinary data
(collected for 12 days) was consistent with plasma da-
ta. The above results suggest the need to reexamine
the current practice of frequent daily dosing and the
use of sustained or controlled release dosage forms of
this drug. The possible cause of reduced plasma clear-
ance of CPM in renal patients is discussed.
Key words: chlorpheniramine; pharmacokinetics,
oral absorption, half-life, bioavailability, volume of
distribution
Pharmacokinetic and pharmacodynamic studies are
important to the development of rational drug ther-
apy. Although chlorpheniramine (CPM) has been
widely used as an antihistamine for more than 3 de-
cades in treating or preventing respiratory or dermat-
Clinical Pharmacology
© Springer-Verlag 1982
ological allergies, its pharmacokinetics and pharma-
codynamics in normal subjects or patients appear not
to have been fully evaluated.
Reported pharmacokinetic parameters from dif-
ferent studies varied considerably. For example, aver-
age peak plasma levels after a 4 mg oral dose were 255
(Lange et al. 1968), 213 (Hanna and Tang 1974) and
5.5 ng/ml (Barhart and Johnson 1977). The volumes
of distribution (Vd area) have been reported to be 0.56
(Thompson and Leffert 1980) and 2.51/kg (Peets et al.
1972) after i.v. dosing and 11.7 (Sanders et al. 1980)
and 7.65 1/kg (Yacobi et al. 1980) (not corrected for
absorption) after oral dosing. To date, it appears that
its absolute bioavailability after oral administration in
humans has not been reported.
The reported long plasma half-lives (t,/2) ranging
from 12 to 36.3 h (Barhart and Johnson 1977; Haefel-
finger 1976; Peers et al. 1972; Sanders et al. 1980;
Thompson and Leffert 1980; Yacobi et al. 1980) ap-
pear not to be in accord with the current practice that
regular dosage forms of CPM be administered 3-4
times a day (US Pharmacopeia 1975) or with the con-
tention that sustained or controlled release dosage
forms are needed for this drug.
It was stated that CPM was readily absorbed oral-
ly with an onset of action in 15 rain, peak effect in i h
and a duration of action for 3-6 h, (Grollman 1962).
However, no convincing data seem available to sup-
port the above statement. On the contrary, the phar-
macological effect using the skin test was shown to
last up to several days after the end of multiple dosing
(Cook et al. 1973). Another interesting question is that
why there is a 20-fold (2-40 mg) difference in the daily
dose recommended for adults (US pharmacopeia
1975). The above review indicates a need to critically
reexamine the pharmacokinetics and pharmacody-
namics of this drug in order to develop a more ration-
al dosage regimen.
0031-6970/82/0022/0359/$01.40
360
The purpose of this study is to evaluate the phar-
macokinetics of CPM in normal adults after i.v. and
oral administration using a specific and sensitive
high-performance liquid chromatographic (HPLC)
assay developed earlier from this laboratory (Athani-
kar et al. 1979), and to discuss its potential clinical sig-
nificance.
Methods
Subjects
Five healthy volunteers (A-E), (1 female and 4 males),
age 274-40 years, body weight 46-72 kg, with no histo-
ry of liver and renal diseases took part in this study.
In tra venous Study
Only subjects A and B were studied. Each received
5 mg of CPM maleate (Chlortrimeton® injection,
Schering Corporation, Keniworth, NJ 07033, USA)
as a bolus dose. Blood samples were collected from
the antecubital vein into heparinized tubes prior to
administration and at 2.5, 5, 10, 20, 30, 45, 60, 90 min
and 2, 4, 6,12, 24, 36 and 48 h after dosing. Urine sam-
ples were collected at 2 h intervals up to 12 h and at
12 h intervals thereafter until 84 h. Plasma and aliquot
of urine samples were kept frozen until analyzed.
Urine pH was measured shortly after sampling.
Single Oral Study
Oral absorption from solution and tablets was eval-
uated. Ten milligrams of CPM maleate (Schering
Corp) dissolved in water (10 ml) was given to subjects
A and B and two 4 mg tablets of CPM maleate (Phil-
lips Roxane Lab Inc, Columbus, OH 43216, USA)
were given to subjects A-E. The oral doses were ad-
ministerd with 200 ml of water after overnight fasting.
Food was withheld for 3 4 h after dosing. Blood sam-
ples were collected prior to drug administration and
at about 30, 45, 60, 90 min and 2, 4, 6, 8, 10, 12, 24, 36
and 48 h after dosing. Urine samples were collected
from subjects D and E.
Multiple Oral Study
Six milligrams of CPM maleate dissolved in water
(6 ml) were administered to subjects D and E two
times a day (9 a.m. and 9 p.m.) for a total of 9 doses.
Blood samples were collected prior to dosing and 3 h
after dosing for the first 3 doses and prior to dosing for
the 8th and 9th doses and at about 0.5,1, 2, 3, 4, 6, 8,12,
24, 36, 48, 60, 72 and 96 h after the last dose. Urine
S. M. Huang et al.: Pharmacokinetics of Chlorpheniramine
samples were collected prior to drug administration
as a control and at 12 h intervals thereafter until 8 days
after the last dose.
Plasma-Blood Cell Partition Study
Three ml of heparinized freshly withdrawn blood
(from subjects A, B, D and E) spiked with stock solu-
tions to obtain blood concentrations of 10, 20, 50 and
100 ng/ml of CPM were incubated at 37 °C and 114
oscillations/rain for 10 min (which was predeter-
mined to be sufficient for equilibration). After centri-
fugation, plasma was separated and kept frozen until
analyzed.
HPLC assay
CPM and its two demethylated metabolites, des-
methyl CPM (DCPM) and didesmethyl CPM
(DDCPM) in plasma and urine were analyzed by the
HPLC method (Athanikar et al. 1979).
Data Analysis
The plasma level-time curves were fitted into poly-
exponential equations using N O N L I N program
(Metzler et al. 1974) with the number of exponents
decided by the MAICE method (Yamaoka et al.
1978). The model-independent pharmacokinefic
parameters were calculated by standard methods
(Athanikar and Chiou 1979; Breimer et al. 1975;
Chiou 1978; Gibaldi and Perrier 1975; Wagner 1976).
Results
Intravenous Study
The plasma level-time curves obtained after i.v. injec-
tion to subjects A and B were best described by tri-
exponential equations (Fig. 1) as judged by MAICE
method (Yamaoka et al. 1978). The values of the in-
itial volume of distribution (Vo), Vd area, Vdss, total
plasma clearance (TBC) and the terminal tv2 and
other model-independent pharmacokinetic parame-
ters are summarized in Table 1. The average blood to
plasma ratio (,~bp) was 1.20 (SD 0.13, n = 13). The ra-
tio was independent of blood concentrations from 20
to 167 ng/ml. Using this ratio, the area under the
curve based on plasma data, AUCp, was converted to
that on blood data, AUCb (Table 1). The fraction of
the oral dose absorbed predicted (Fpre) from the i.v.
studies (Table 1) were 0.94 and 0.93 for subjects A and
B, respectively. The plasma levels of DCPM and
DDCPM were not measurable after i.v. studies.