Beruflich Dokumente
Kultur Dokumente
PHARMACO-
KINETICS
Assoc. Prof. I. Lambev
Medical University of Sofia
www.medpharm-sofia.eu
(Abstract)
Pharmacokinetics
– how does the
human body
act on the drugs?
Pharmacokinetics is the quantitative study of
drug movement in, through and out of the body.
Intensity of effect is related to the concentration
of the drug at the site of action, which depends
on its pharmacokinetic properties.
All pharmacokinetics processes involve transport
of the drug across biological lipid membrane.
[AH]
pKa = pH + log10 ------
[A ]
-
pKa is the negative logarithm of acidic dissociation
constant of the week electrolyte. If the concentration
of unionized drug [AH] is equal to concentration of
ionized drug [A-], then
[AH]
--------- = 1
[A-]
since log 1 is 0, under this condition pH = pKa
In this case the molecules of drugs are 50% ionized.
For a week base:
[BH+]
pKb = pH + log10 ------
[B]
Filtration
Filtration is passage of a drug through aqueous pores
in the membrane through paracelullar spaces.
The moving force is hydrostatic or osmotic pressure.
Lipid insoluble drugs cross the biomembrane by
filtration only if their molecular size is smaller than
the diameter of the enlarged aqueous pores.
The filtration has an importance mainly at the level
of renal glomerulus, where the size of capillaries have
large pores (40 Å) and most drugs (even albumin)
can filtrate. The brain capillary pores have small size.
Carrier transport –
by combination with a carrier molecule which acts as
a ferry-boat across the lipid region of the membrane.
Carrier transport is saturable and competitively
inhibited by analogues which utilize the same carrier.
- ileum (B12, A, D, E, K)
- large intestine
(water, Na , Cl , K )
+ - +
Drugs can also alter absorption by gut wall effect:
altering motility (atropine, amitriptyline, pethidine,
methoclopramide) or causing mucosal damage
(neomycin, methotrexate, reserpine, vinblastine).
Alteration of gut flora by antibiotics may disrupt the
enterohepatic recirculation of oral contraceptives
and digoxin.
S.c. and i.m. application
By these routes the drug is deposited in the vicinity of
the capillaries. Lipid soluble drugs pass readily across
the whole surface of the capillary endothelium, but
very large molecules are absorbed through lymphatics.
Many drugs not absorbed orally are absorbed parenterally.
Absorption from s.c. site is slower than that from i.m. site,
but both are generally faster and more predictable than
p.o. absorption. Application of heat and muscular exercise
accelerate drug absorption by increasing blood flow.
Application of vasoconstrictors (e.g. adrenaline) retard
absorption. Many depot preparations (preparations with a
long action), such as benzatine benzylpenicillin and
protamine zinc insulin can be given by these routes.
Topical applications
(skin, cornea, mucous membranes)
Systemic absorption depends on lipid solubility.
Only a few drugs significantly penetrate intact skin.
Nitroglycerine, hyoscine (scopolamine) and estradiol
have been used in this manner. Glucocorticosteroids
(GCS) applied over extensive areas can produce
systemic effects and pituitary-adrenal suppression.
(p.o. application)
0 5 10 15
Time (h)
Plasma concentration time curves of the three preparations of a drug
which contain the same amount. Formulation B is more slowly absorbed
than A and may not produce therapeutic effect. Formulation C is absorbed
to a lesser extent (it has lower bioavailability).
II. DISTRIBUTION
In studying the pharmacokinetics biosystems
conditionally divided into separate parts –
compartment (or phases).
They are virtual spaces in which the drug
is evenly distributed. They are distinguished
each other in the volume of distribution
and invasion (penetration) and
evazionnite (release) rate constants.
The distribution of the drugs is a dynamic process,
during which they pass from the central (plasma)
compartment in the tissue to reach steady state
(steady state – ss). It depends on the mode of
administration and the pK of the drug, its ability
for binding to plasma protein, pH of the medium,
organ perfusion.
The number of compartments is determined for
each drug according to the experimental data
measured concentrations at different moments
in the blood, urine and body fluids.
Two-compartment pharmacokinetic model
Body fluid compartments
The total body water as a percentage of body
mass varies from 50% to 70%, being rather
less in women than in man.
Body water is distributed
into the following main compartments:
1. plasma (5% of body mass)
2. intestinal fluid (16%)
3. intracellular fluid (35%)
4. transcellular fluid (2%)
5. fat (20%)
Apparent volume of distribution (Vd)
It is accept that the body behaves as a single
homogeneous compartment with volume (Vd)
in which the drug gets immediately distributed:
Dose administered
Vd = -----------------------------
Plasma concentration
Drugs extensively bound to plasma proteins are largely
restricted to the vascular compartment and have low Vd
(e.g. warfarin – 99% bound and its Vd is 0,1 L/kg).
МАО COMT
70% 27–29%
CYP3A4/5 CYP1A2
CYP2C19
CYP2C8/9/18 CYP2E1 CYP2D6 CYP1A1
CYP2B6 CYP2A6
(30–50%) ~15% <5%
<5% <5% ~20% ~10%
Inhibitors:
Methoxsalen Fluconazole Sulphaphenazole Ketoconazole Furafylline Tetrahydro- Quinidine
Gestodene Fluvoxamine furane
Inducers:
Phenobarbital Phenobarbital Phenobarbital Omeprazole Ethanol
Pheno- Nicotine Isoniazid
Rifampicin Rifampicin Rifampicin
barbital
Dexamethasone
Carbamazepine
Barbiturates, phenothiazines, paracetamol, streroids,
phenytoin, benzodiazepines, theophyllin and many other
drugs are oxydaized by CYP450. Some other drugs
(adrenaline, mercaptopurine) and ethanol are oxidized
by mitochondrial or cytoplasmic enzymes.
b) Reduction. This reaction is conversed
of oxidation and involves CYP450 enzymes
working in the opposite direction.
Drugs, primarily reduced, are
chloramphenicol, halothane.
c) Hydrolysis. This is cleavage of a drug molecule by
taking up a molecule of water.
Esterase
Ester + H20 Acid + Alcohol
Similarly amides and polypeptides are hydrolyzed
by amidase and peptidases. Hydrolysis occurs in the liver,
intestines, plasma, and other tissues. Examples are
choline esters, procaine, lidocaine, pethidine, oxytocin.
d) Cyclization is formation of a ring structure from a
straight chain compound, e.g. proguanil.
e) Decyclization is opening up of a ring structure of
the cyclic molecule, e.g. phenytoin, barbiturates.
Phase II – synthetic (conjugation) reactions
These involve conjugation of the drug or its phase I meta-
bolite with an endogenous substrate to form a polar highly
ionized organic acid, which is easily excreted in urine or
bile. Conjugation reactions have high energy requirements.
(1) Glucoronide conjugation is the most important syn-
thetic reaction. Compounds with a hydroxyl or carboxylic
acid group are easily conjugated with glucuronic acid,
which is derived from glucose, e.g. chloramphenicol,
aspirin, morphine, metronidazole, GCS, bilirubin, thyroxine.
Drug glucuronides, excreted in bile, can be hydrolyzed
in the gut by bacteria, producing beta-glucuronidase.
The liberated drug is reabsorbed and undergoes the same
fate. This enterohepatic recirculation of some drugs (e.g.
chloramphenicol, phenolphthalein, oral contraceptives)
prolongs their action.
(2) Acetylation. Compounds having amino or hydrazine
residues are conjugated with the help of acetyl CoA, e.g.
sulfonamides, isoniazid. Multiple genes control the acetyl
transferases and rate of acetylation shows genetic
polymorphism (slow and fast acetylators).
(3) Sulfate conjugation. The phenolic compounds and
steroids are sulfated by sulfokinases, e.g.
chloramphenicol, adrenal, and sex steroids.
The two phases of drug metabolism
Synthetic (conjugation) reactions:
(4) Methylation. The amines and phenols can be
methylated. Methionine and cysteine act as methyl donors.
Examples: adrenaline, histamine, nicotinic acid.
(5) Ribonucleoside/nucleotide synthesis is important
for the activation of many purine and pyrimidine antimeta-
bolites used in cancer chemotherapy, e.g. Xeloda®.
(6) Only a few drugs are metabolized by enzymes of
intermediary metabolism. Examples:
•alcohol by dehydrogenases
•allopurinol by xanthine oxidase
•succinylcholine and procaine by plasma cholinesterase
•adrenaline by monoamine oxidase (MAO)
FIRST PASS (PRESYSTEMIC) METABOLISM
This refers to metabolism of a drug during its passage
from the site of absorption into systemic circulation. All
orally administered drugs are exposed to drug metabo-
lism in the intestinal wall and liver in different extent.
•High first pass metabolism: propranolol, verapamil,
pethidine, salbutamol, nitroglycerine, morphine, lidocaine.
•Oral dose of these drugs is higher than sublingual or
parenteral dose.
•There is individual variation in the oral dose due to
differences in the extent of first pass metabolism.
•Oral bioavailability is increased in patients with severe
liver disease.
IV. EXCRETION
Excretion is the passage out of
systematically absorbed drugs.
Drugs and their metabolites
are excreted in:
urine (through the kidney)
•bile and faeces
•exhaled air
•saliva and sweat
•milk
•skin
The kidney is responsible for excreting all
water soluble substances.
Glomerular filtration. Glomerular capillaries have large
pores. All nonprotein bound drugs (lipid soluble or insoluble)
presented to the glomerulus are filtrated. Glomerular filtration
of drugs depends on their plasma protein binding and renal
blood flow. Glomerular filtration rate (g.f.r.) declines
progressively after the age of 50 and is low in renal failure.
Tubular reabsorption. Lipid soluble drugs filtrated at the
glomerulus back diffuse in the tubules because 99% of
glomerular filtrate is reabsorbed, but nonlipid soluble
and highly ionized drugs are unable to do so.
Thus, the rate of excretion of such drugs, e.g.
aminoglycoside (amikacin, gentamicin, tobramycin) parallels
g.f.r. Changes in urinary pH affect tubular reabsorption of
partially ionized drugs:
•Weak bases ionize more and are less reabsorbed
in acidic urine.
•Weak acids ionize more and are less reabsorbed
in alkaline urine.
This principle is utilized for facilitating elimination
of drugs in poisoning:
•Urine is acidified in morphine and atropine poisoning.
•Urine is alkalized in barbiturate and salicylate poisoning.
The effect of changes in urinary pH on drug excretion
is greatest for a drug having pK values between 5 to 8,
because only in this case pH dependent passive
reabsorption is significant.
Tubular secretion is the active transfer of organic acid
and bases by two separate nonspecific mechanisms,
which operate in the proximal tubules:
•Organic acid transport for penicillins, probenecid,
salicylates, uric acid, sulfinpyrazones, nitrofurantoin,
methotrexate, drug glucuronides, etc.
•Organic base transport for thiazides, quinine,
procainamide, cimetidine, amiloride, etc.
Many drug interactions occur due to competition
for tubular excretion, e.g.:
•Aspirin blocks uricosuric action of probenecid and sulfin-
pyrazone and decreases tubular excretion of methotrexate.
•Probenecide decreases the urine concentration of
nitrofurantoin, increases the duration of penicillin action
and impairs excretion of methotrexate.
•Quinidine decreases renal and biliary clearance of digoxin
by inhibiting efflux carrier P-gp.
Tubular transport mechanisms are not well developed
at birth. Duration of action of many drugs (penicillins,
cephalospoins, aspirin, etc.) is longer in neonates.
These systems mature during infancy.
•aminoglycosides
•beta-lactams
•sulfonamides
•quinolones
•nitrofurans
•polymyxins
•macrolides
•lincosamines
•rifampicin
•tetracyclines (p.o.)
•General inhalation
anaesthetics
•Potassium iodide
•Broncho-
antiseptic oils
•Alcohol
•sulfonamides
•barbiturates
•reserpine
•alcohol
•Coffeinum
(Caffeine)
Rauwolfia serpentina
(Reserpine: India)
Saliva excretion
•oleandomycin
•spiramycin
•phenytoin
•zalcitabine
•verapamil
Morphine
(10% stomach excretion)
•morphine pKb: 7.9
•stomach pH: 1–2
•plasma pH: 7.36
Poppy
KINETICS OF ELIMINATION
(elimination = metabolism + excretion)
Clearance (Cl) of a drug is the theoretical volume of plasma
from which the drug is completely removed per unit time:
Cl = Rate of elimination/Plasma concentration
Renal (Clr) or creatinine clearance (Clcr):
Curine x Vurine
Clrenal = --------------------
Cplasma
First order (exponential) kinetics. For majority of drugs
the processes involved in elimination are not saturated
over the clinically obtained concentrations. These drugs
have first order kinetics. Their rate of elimination is
directly proportional to plasma drug concentration and
their clearance
remains constant.
Semilog plasma
concentration-time
plot of a drug eli-
minated by first
order kinetics
after i.v. injection.
Zero order (linear) kinetics.
In a few cases where the drugs are inactivated
by metabolic degradation (such as ethanol,
phenytoin, theophylline, salicylates, and warfarin),
the time-course of disappearance of the drug from
the plasma does not follow the exponential or
biexponential pattern, but is initially linear.
These drugs are removed at a constant rate
which is independent of plasma concentration.
This is often called zero order kinetics.
The blood alcohol
concentration
falls linearly and
the rate of fall
does not vary
with dose.
Plasma half live (t1/2) is the time in which the plasma
concentration of a drug declines by one half. Drug with
long t1/2 can accumulate. Plasma t1/2 of some drugs:
Adenosine < 2 sec
Dobutamine – 2 min
Benzylpenicillin – 30 min
Amoxicillin – 1 h
Paracetamol – 2 h
Atenolol – 7 h
Diazepam – 40 h
Ethosuccimide – 54 h
Digitoxin – 168 h
From the peak plasma concentration the drug is vir-
tually eliminated from the plasma in 5 t1/2 periods: