Course Title: BIC 409

Course Description:
Xenobiochemistry

Department of Biochemistry
College of Medicine
University of Ibadan, Nigeria
 Factors affecting Drug Metabolism

1)Environmental factors
• Induction
• Inhibition
2)Disease factors
3)Age and Sex
4)Species and strain differences
5)Hereditary or genetic factors
6)Drug administration route
 Environmental factors
Activity of most drug metabolizing enzymes
can be modulated by exposure to certain
exogenous compounds
•Drugs
•Dietary micronutrient (food additives,
nutritional or preservative)
•Environmental chemicals (pesticides,
industrial chemicals)
Effects of these compounds can lead to
induction or inhibition
It can contribute to inter-individual variability
in the metabolism of many drugs
 Induction of Drug Metabolism
Enzyme induction is the process by which
exposure to certain substrates (e.g., drugs,
environmental pollutants) results in
accelerated biotransformation with a
corresponding reduction in unmetabolized
drug.
(some substance stimulates the synthesis of
the enzyme and the metabolic capacity is
increased -drug gets metabolized faster).
Many drugs, and environmental chemicals
enhances the metabolism of themselves or other
co-ingested compounds leading to alteration in
their pharmacologic and toxicologic effects.

It is a dose-dependent phenomenon.

This mainly occur by inducing transcription of

CYP450 mRNA which leads to overproduction
of these enzymes in the liver and other extra-
hepatic tissues.
Enzyme inducers:
Many drugs have the ability to stimulate the
activity of CYP450 isoforms.
Many environmental chemicals also alter the
activity of CYP450 isoforms:
•Cigarette smoking.
•Polycyclic aromatic hydrocarbons.
•Xanthines and flavones in food.
•Halogenated hydrocarbons in insecticides.
•Food additives.
These chemicals do not have something in
common except they are all metabolized by one
or more CYP450 isoforms.
 Consequences of Induction

Increased rate of metabolism

Decrease in drug plasma concentration
Enhanced oral first pass metabolism
Reduced bioavailability
If metabolite is active or reactive,
increased drug effects or toxicity
Therapeutic Implications of Induction

Most drugs can exhibit decreased efficacy

due to rapid metabolism.

Drugs with active metabolites can display

increased drug effect and/or toxicity due to
enzyme induction.

Dosing rates may need to be increased to

maintain effective plasma concentrations.
 Inhibition of Drug Metabolism

Drug metabolism is an enzymatic process

can be subjected to inhibition.

Drugs and other substances can inhibit the

metabolism of other drugs.
 Types of inhibition
Competition between substrates for enzyme
active site
•Concentration of substrates
•Affinity for binding site (drug with high affinity
for an enzyme will slow the metabolism of any
low affinity drug)
•Irreversible inactivation of enzyme
•Complex with heme iron of CYP450 (cimetidine,
ketoconazole)
•Destruction of heme group (secobarbital)
•Depletion of cofactors such as NADH2 for phase
II enzymes
Inhibition can be divided into three major
categories:
1)Reversible inhibition.
2)Metabolite intermediate complexation of
CYP450.
3)Mechanism-based inactivation of CYP450.

Reversible inhibition: is a result of reversible

interaction at the heme-iron active centre of
CYP450, the lipophilic site or both.
This action will be abolished once the enzyme
inhibitor is discontinued.
Examples: fluoroquinolones, cimetidine, azoles
antifungal agents.
Metabolite-intermediate complexation of
CYP450:
Happens when the metabolite of certain drugs
forms stable covalent bond with the reduced
ferrous heme intermediate.
Alkylamines are examples of such drugs due to
the formation of the nitroso metabolite:
R N R N R N O
H OH R N

CYP450----Fe

OH
R N
Fe
CYP450
Mechanism-based inhibition (suicide
inhibition):

Some drugs contain functional groups that

when oxidized by CYP450 generate
metabolites that bind irreversibly to the same
enzyme.
Examples:
Alkane and alkenes containing drugs can
form radical intermediate after oxidation
with CYP450 which subsequently leads to
alkylation of the heme moiety.
 Consequences of Inhibition
• Increase in the plasma concentration of parent
drug
•Reduction in metabolite concentration
•Exaggerated and prolonged pharmacological
effects
•Increased likelihood of drug-induced toxicity
 Therapeutic Implications of Inhibition
•The increase in the cellular level of Second
Messenger subsequently leads to a rapid
alteration in cellular function.
•May occur rapidly with no warning
•Particularly effects drug prescribing for
patients on multidrug regimens
•Knowledge of the CYP450 metabolic pathway
provides basis for predicting and understanding
inhibition.
 Disease Factors
Liver Disease – Cirrhosis, Alcoholic liver disease,
jaundice, carcinoma. It is a major location of drug
metabolizing enzymes.
Dysfunction can lead to impaired drug
metabolism-decreased enzyme activity
First pass metabolism affected – may increase
2-4 times bioavailiability
Results in exaggerated pharmacological responses
and adverse effects.
Cardiac failure causes decreased blood flow to the
liver. Hormonal diseases, infections and
inflammation can change drug metabolizing
capacity.
 Age
Newborns and infants – metabolize drugs
relatively efficiently but at a rate generally
slower than adults
 Full maturity appears in second decade of
life
 Slow decline in function associated with
aging.

It is well documented that the metabolism of

many drugs and their elimination is impaired in
the elderly.
In elderly there are many physiologic changes
that affect the plasma concentration and renal
clearance which often lead to decrease in the
hepatic blood flow, glomerular filtration, hepatic
enzymes activity and plasma protein binding.

First pass metabolism of many drugs is reduced in

elderly patients: such drugs are diazepam,
theophylline, morphine, propranolol and
amitriptyline.

All of the common phase-II enzymes are affected

by aging.
The human fetus has only the cytochrome P450
monooxygenase 3A (CYP 3A)which is capable of
metabolizing xenobiotics during the first part of
gestation.

Placenta of tobacco smokers has shown increase

of CYP1A activity that will form toxic metabolites
which will covalently bind to fetus
macromolecules leading to teratogenic and
hepatotoxic effect.

Phase-II enzymes are found in low to negligible

concentration in the fetus leading to high risk of
toxicity by pregnant metabolites.
The ability to carry out metabolic reactions
increases after birth and approaches adult levels
in about 1 to 2 months.

The inability of infants to conjugate

chloramphenicol with glucuronic acid appears to
be responsible for the accumulation of toxic
levels of this drug. This will lead to what is called
gray-baby syndrome.

Neonatal hyperbilirubinemia results from the

newborn baby to glucuronide bilirubin.
 Species and strain differences

There are metabolic differences between species, such as

between human and dogs, rabbit, pigs, cats and birds.
O

OH
(in man, rabbit and guinia pig
O

NH2

Amphetamine

(in rat)
NH2
HO
The conjugation with amino acids differs between
species as well:

Glycine conjugation is common in most animals.

Birds normally use ornithine amino acid for
conjugation.

Strain differences in mice and rabbit have been

noted: mainly due to genetic variations that affect
the amount of metabolizing enzymes
 Sex
The rate of metabolism also varies according to
sex in some animal species. Responsiveness to
certain drugs is different for men and women

Generally it is species dependent:

Rabbit and mice do not show a significant sex
differences in drug metabolism.

In humans, few repots of sex differences have

been observed:
Nicotine and aspirin seem to be metabolized
more rapidly in male compared to female.
Pregnancy – induction of certain drug
metabolizing enzymes occurs in second and
third trimester.

Hormonal changes during development have

a profound effect on drug metabolism
 Hereditary or genetic factors
Genetic factors in human is the main cause for the
differences in the rate of drug metabolism.
• The difference in the rate of acetylation is one
example:
• Rapid acetylators have more hepatic acetyl N-
transferase than the slow acetylators.
• 90% of Asians and Eskimos are rapid
acetylator.
• Egyptians and Mediterranean are slow
acetylators.
The rate of acetylation is clinically important in
terms of therapeutic response and toxicity.

Also, genetic factors affect the arte of

oxidation.
wide variability in the response to drugs
between individuals.

Consequences of such variation may be

therapeutic failure or an adverse drug reaction.
• CYP2D6 is extensively studied. The gene for
CYP2D6 is highly polymorphic.
• It’s expression leads to 3 phenotypes (phenotype
is the expression of genetic make-up)
• Extensive metabolizers (EMs) have
functional enzyme activity
• Intermediate metabolizers (IMs) have
diminished enzyme activity
• Poor metabolizers (PMs) have little or no
activity
• 5-10% of Caucasians and 1-2% of Asians
exhibit the PM phenotype
Debrisoquine, formerly used in the treatment of
hypertension, is metabolized by CYP2D6 to 4-
hydroxydebrisoquine.

Remarkable inter-individual variation in

pharmacological effect of the drug.

Urine of volunteers given debrisoquine was

examined for presence of 4-hydroxydebrisoquine
One subject had a very low conversion of parent
drug to metabolite and was very sensitive to the
antihypertensive effects of debrisoquine
 Drug administration route
1)Orally administered drugs are absorbed from the GIT
and transported to the liver before entering the systemic
circulation. Thus the drug is subjected to hepatic
metabolism (first pass effect) before reaching the site of
action.

2)Sublingually and rectally administered drugs take

longer time to be metabolized than orally taken
drugs.Nitroglycerine is ineffective when taken orally due
to hepatic metabolism.

3)IV administration avoid first pass effect because the

drug is delivered directly to the blood stream.