Download Drug elimination (metabolism, excretion)

Drug elimination
(metabolism, excretion)
Anton Kohút
DRUG METABOLISM
major site of drug metabolism – liver,
exceptions:
- suxamethonium and procaine
- plasma cholinesterase
- tyramine - intestinal wall

Phase 1
- lipophilic molecules
are converted
into more polar molecules
Reactions are catalyzed by the
cytochrome P-450 (CYP)
by:  oxidation
 reduction
 hydrolysis
- products are often less eactive
than the parent compounds
- after metabolism may be
excreted by kidneys
- each of the enzyme has a low
specificity
Phase 2


consists of conjugation reactions
Most often involved groups in
conjugation are:
 glucuronyl
 sulphate
 methyl
 acetyl
 glycyl
 glutamyl
The two phases of drug metabolism
Metabolism of imipramine
Involvement of some isoform of CYP
in the metabolism
FACTORS INFLUENCING DRUG
METABOLISM
- systemic pathological processes - liver
diseases, heart failure
 - age
 - sex
 - body temperature
 - genetic factors - polymorhism
 - drug interactions enzyme inhibition,
enzyme induction

Drug interactions - enzyme induction

Drug induction
increase of enzyme activity
can decrease drug potency,
- result is an increased synthesis
of microsomal enzymes after
repeated use of drugs
- generally, metabolism of
inducers itself is increased as
well as various other
compounds,
- increase of metabolism may
increase toxicity of
paracetamol – toxic
metabolites


Drugs that cause
induction
barbiturates,
carbamazepine, ethanol
(chronic use),
glutethimide,
griseofulvin,
meprobamate,
phenytoin,
rifampicin,
sulphinpyrazone,
Drug interactions - enzyme inhibition

Drug inhibition
- enzyme inhibition
can slow down the
metabolism
- action of
coadministrated
drug may be
increased and
prolonged
Drugs that cause
inhibition
- cimetidine,
- erythromycin,
- quinolone
- sodium valproat,
- allopurinol

Genetic polymorphism
Genetic polymorphism
Genetic polymorphism
1. Plymorphism in acetylation (rapid or slow
acetylators – isoniasid (INH), hydralazine and
procainamide, sulphasalazine
2. Poor oxidisers – debrisoquine, metoprolol, timolol,
haloperidol
3. Glucose-6-phosphate dehydrogenase deficiency
G-6-PD – risk of haemolysis – aspirin, probenecid,
quinine, chloroquine, nitrofurantoin, some
sulphonamides
4. Pseudocholinesterase deficiency – malignant
hyperthermia – suxametonium,

CYP 2D6
Drug excretion

Drug excretion
- Drugs are exreted : either unchanged or as
metabolites.
- Lipid-soluble drugs are not readily eliminated
until they are metabolized to more polar
compounds
Renal excretion
Extrarenal excretion
Renal excretion
1. Glomerular filtration - passive
Depends on: fractional plasma protein binding

glomerular filtration rate (size of molecules)

(MW 68 000) is completely held back

by this way is removed about 20% of drugs from the blood
2. Passive tubular reabsorption
  the nonionized forms of weak acids and bases undergo
passive reabsorption.
 The concentration gradient for back-diffusion is created by
the reabsorption of water with Na+ and other inorganic ions.

When the tubular urine is made more acidic, the
excretion of weak acids is reduced (alkalinization
of the urine have the opposite effects on the
excretion of weak bases).

Treatment of drug poisoning, the excretion of
some drugs can be hastened by appropriate
alkalinization or acidification of the urine.
Renal excretion (cont.)
3. Active tubular secretion
Many organic acids (such as penicillin) and metabolites
(such as glucuronides) are transported by the system that
secretes naturally occurring substances (such as uric acid).
 Organic bases, such as tetraethylammonium, are
transported by a separate system that secretes choline,
histamine, and other endogenous bases.
 The carrier systems are relatively nonselective, and
organic ions of similar charge compete for transport.
Both transport systems also can be bidirectional, and at
least some drugs are both secreted and actively
reabsorbed. (an endogenous organic acid is uric acid).
Excretion by other routes
Biliary and fecal excretion
 Saliva, sweat, tears - the concentration of
some drugs in saliva parallels that in
plasma.
 Breast milk - excretion by breast milk is
dependent mainly upon diffusion, Milk is
more acidic than plasma, basic compounds
may be slightly concentrated in this fluid.

Excretion by Other Routes
1. Saliva
 Excretion of drugs into sweat, saliva, and tears is
quantitatively unimportant.
 Excretion by saliva is dependent mainly upon diffusion
 Drugs excreted in the saliva enter the mouth, where they
are usually swallowed.
 The concentration of some drugs in saliva parallels that in
plasma.
 Saliva may therefore be a useful biological fluid in which
to determine drug concentrations when it is difficult or
inconvenient to obtain blood.

2. Breast milk
 Excretion by breast milk is dependent mainly
upon diffusion
 Milk is more acidic than plasma, basic compounds
may be slightly concentrated in this fluid,
 Nonelectrolytes, such as ethanol and urea,
readily enter breast milk and reach the same
concentration as in plasma, independent of the pH
of the milk.
 Excretion of drugs in breast milk are potential
sources of unwanted pharmacological effects in
the nursing infant.

3. Feces
 Substances excreted in the feces are mainly
unabsorbed orally ingested drugs or
metabolites excreted in the bile and not
reabsorbed from the intestinal tract.
 4. Biliary excretion

Elimination
Rate of elimination
Elimination of most drugs from the body
after therapeutically relevant doses
follows first-order kinetics.
To illustrate first order kinetics we might
consider what would happen if we were
to give a drug by i.v. bolus injection,
collect blood samples at various times and
measure
the plasma concentrations of
the drug. We might see a decrease in
concentration as the drug is eliminated.
First-order kinetics
Elimination half-life (t1/2)
Definition: Elimination half-life is the time
it takes the drug concentration in the
blood to decline to one half of its initial
value.
It is a secondary parameter :
The elimination half-life is dependent on the
ratio
of VD and CL.
Unit : time (min, h, day)
First order kinetics half - life




 Most drugs exhibit first order kinetics – disappeaance
of drug from plasma follows exponential patterns.
 The rate of elimination is directly proportional to
drug concentration.
 Plasma half-life is directly proportional to the volume
of distribution and inversely proportional to the overall
rate of clearance
 With repeated dosage or sustained delivery of a drug
the plasma concentration approaches a steady state
within 4-5 half-lifes.
Rate of elimination
Elimination which follows first-order kinetics:
dC/dt
=
k
.
C
el
Dose=100 mg, V =10 L,
Conc. (mg/L)
10
d
C0=Dose/Vd = 10 mg/L
7.5
5
5
2.5
2.5
1.25
0.625
0
0
2
4
6
time (h)
8
10
kel …. rate constant
of elimination
rate of change
is proportional to
concentration and is
therefore decreasing
with time as the
conc. decreases
Rate of elimination
monoexponential decay: C(t) = C0 . e- kel . t
Conc. (mg/L)
half-life : t1/2
Dose=100 mg, Vd=10 L,
C0=Dose/Vd = 10 mg/L
10
7.5
C= C0 / 2
5
5
t= t1/2 = ln2 / kel
= 0.693/ kel
2.5
2.5
1.25
0.625
0
after 4 half-lives:
0
2
4
6
time (h)
8
10
6% remaining,
94% eliminated
Saturation kinetics



 In a few cases as
ethanol, phynytoin and
salicylate
disapppearance of drug
from plasma does not
follow exponential
patterns.
 Pattern of
desappearance of drug is
linear – drug is removed
at a constant rate that is
indipendent of plasma
concentration
 This is often called zero
order kinetics
Use of t1/2:
1/ t1/2 can be used to predict how long it will take
for the drug to be eliminated from plasma.
1.
Conc. (mg/L)
10
2.
50
7.5
5
4.
3.
5.
87.5
94 97
75
percent eliminated %
t1/2 = 2 hours
5
2.5
2.5
1.25
0.625
0
0
2
4
6
time (h)
8
10