factors affecting biotransformation

1. Factors affecting
Biotransformation
PRESENTED BY DR. MUHAMMAD USAMA(PGR PHARMACOLOGY)

2. TYPES OF FACTORS
Chemical
Altered
Physiological
Route of Drug
Administration
Envirnmental
Temporal
Biological

3. Chemicalfactors
Enzyme induction
Enzyme inhibition

4. Enzyme Induction
 Results in increased metabolism and decreased pharmacological action
of drug.
Examples:
1.Rifampicin If taken by female patients taking
contraceptives, causes decreased therapeutic effect, leading to
pregnancy.
2.Phenobarbitone If administered to patients taking warfarin, may
cause therapeutic failure, leading to increased bleeding
tendency.

5. Enzyme Inhibition
 Results in decreased drug metabolizing ability of cytochrome P450
Enzymes and increased pharmacologic action of the drug.
 Competition for the active sites
takes place between the inhibitor and the
drugs. E.g.
1.Sulfonamides decrease the metabolism of phenytoin so that its
blood levels become toxic.
2.Cimetidine decreases the metabolism of propranolol leading to
enhanced bradycardia.

6. Biological Factors
Age Gender Genetic
Race Diet

7. AGE
In infants microsomal enzyme system is not fully
developed. So the rate of metabolism is very low.
1. Chloramphenicol does not have great efficacy in
infants. Toxic effects in the form of grey baby
syndrome might occur. The baby may be
cyanosed, hypothermic, flaccid and grey in color.
Shock and even death might occur if toxic levels
get accumulated.
2. Diazepam may result in floppy baby syndrome in
which flaccidity of the baby is seen.

8. AGE
 In elderly, most processes slow down
which leads to decreased metabolism.
Shrinkage of organs occurs as well
along with decreased liver functions
and decreased blood flow through the
liver. All these factors decrease the
metabolism.
 The drug doses should be adjusted in
the elderly

9. GENDER
 Gender related differences in the rate of metabolism are attributed to sex
hormones and are generally observed following puberty.
 Male have a higher BMR as compared to the females, thus can
metabolize drugs more efficiently, e.g. salicylates and others might
include ethanol, propranolol, benzodiazepines.
 Women on oral contraceptives metabolize drugs at a slower rate

10. GENETICS
 Drugs behave differently in different individuals due to
genetic variations
 Succinyl choline, which is a skeletal muscle relaxant, is metabolized
by pseudocholine esterase. Some people lack this enzyme, due to
which lack of metabolism of succinyl choline might occur. When
administered in those individuals, prolonged Apnea might result.
 Different groups of populations might be classified as fast
metabolizers and poor metabolizers of drugs.
For drugs, like Isoniazid, fast acetylators as well as slow acetylators
are present. Fast acetylators cause rapid acetylation, while poor
metabolizers metabolize less. Hepatic acetyl transferrase catalyzes
acetylation. Slow acetylation might occur due to genetic
malformation leading to toxic levels of drug.

11. GENETICS(cont.)
Syndromes
 Crigler-Najjar type I
 Crigler-Najjar type II
 Gilbert’s syndrome
Problems
 Complete lack of bilirubin
glucuronidation(No UGTIAI
expression)
 Low amounts of bilirubin
glucuronides(UGT1A1 expression
present at reduced level)
 • Mutation in the UGT1A1*28 gene
promoter
• Reduced capacity of UGT1A1 to
metabolize drugs
• Subjects are at risk of ADR to different
drugs like Simvastatin, Atorvastatin etc

12. RACE/SPECIES
 Asians, Orientals, Blacks and Whites might have different drug
metabolizing capacity. Examples include difference in drug metabolizing
capacity of certain anti malarial.
 Eskimos metabolize drugs faster than Asians.
 Laboratory animals can metabolize drugs faster than man e.g.
barbiturates.

13. DIET
 The enzyme content and activity is altered by a number of dietary
components.
 Low protein diet decreases and high protein content in diet increases the
drug metabolizing ability.
 Dietary deficiency of vitamins and minerals retard the metabolic activity of
enzymes.

14. Altered Physiological Factors
Pregnancy
Hormonal
Imbalance
Disease
states

15. PREGNANCY
 During pregnancy, metabolism of some drugs is increased while that of
others is decreased due to the presence of steroid hormones e.g.
 Phenytoin
 Phenobarbitone
 Pethidine

16. HORMONAL IMBALANCE
 Higher levels of one hormone may inhibit the activity of few enzymes
while inducing that of others. E.g.
 Hypothyroidism decreases drug metabolizing capacity (increased half life
of antipyrine, digoxin, methimazole, practolol) while hyperthyroidism
increases it.

17. DISEASE STATES
 Liver disease such as hepatic carcinoma, cirrhosis, hepatitis, obstructive
jaundice etc. reduce the hepatic drug metabolizing ability and thus
increase the half lives of almost all drugs.
 In renal diseases conjugation of salicylates, oxidation of vitamin D and
hydrolysis of Procaine are impaired.
 Cardiovascular diseases, although have no direct effect, decrease the
blood flow, which may slow down biotransformation of drugs like
isoniazid, morphine and propranolol.
 Pulmonary conditions may decrease biotransformation. Procaine and
procainamide hydrolysis is impaired.

18. TEMPORAL FACTOR
 Diurnal variations and variations in enzyme activity with light cycle is
circadian rhythm.
 Enzyme action is maximum during early morning and minimum in late
afternoon which is probably due to variation in cortisol levels.

19. ROUTE OF ADMINISTRATION
 Oral route can result in extensive hepatic and intestinal metabolism of
some drugs (first pass effect).
 Lignocaine is almost completely metabolized if taken by oral route
therefore the preferable route is Topical.

20. ENVIRONMENTAL FACTORS
 Aromatic hydrocarbon contained in Cigarette smokers act as enzyme
inducers.
 Chronic alcoholism might lead to enzyme induction as well.
 Pesticides or Organophosphate insecticides may act as enzyme inducers.
 In hot and humid climate biotransformation is decreased and vice versa.
 At high altitude decreased biotransformation occurs due to decreased
oxygen leading to decreased oxidation of drugs.