Pharmacology - Drug Metabolism

1. Prepared by:
JANINE JAYVEE N. RAMOS
MMSU-COM Class 2021
CLINICAL RELEVANCE OF DRUG
METABOLISM

2. OUTLINE
• Diet and Environmental Factors
• Age and Sex
• Drug-Drug Interactions during Metabolism
• Interactions between Drugs and Endogenous
Compounds
• Diseases Affecting Drug Metabolism

3. Diet and Environment
DIET Charcoal-broiled foods and
cruciferous vegetables
Grapefruit juice
 Known to INDUCE
CYP1A enzymes
 Known to INHIBIT
CYP3A metabolism of
co-administered drug
substrates
CIGARETTE
SMOKING
Smokers vs Nonsmokers
 Cigarette smokers metabolize some drugs more
rapidly than nonsmokers because of enzyme
induction
WORKPLACE Exposure to pesticides
 Industrial workers exposed to some pesticides
metabolize certain drugs more rapidly than
unexposed individuals

4. Age and Sex
Very Young Elderly
 Not fully ‘metabolically
competent’
 Virtually no Phase II metabolism
(chloramphenicol toxicity due to
poor glucuronidation – Gray Baby
Syndrome)
 Limited Phase I enzyme activity
 CYP3 activity only e.g. Codeine
metabolism
 Capacity increases during
development
 Men and women older than 65-70
years have significantly decreased
drug metabolism
 Diminished enzyme induction
 Are on many drugs, around 5, and
so there is the possibility of drug-
drug interactions
Male vs Female
 Young adult male rats metabolize drugs much faster than mature female
rats or pre-pubertal male rats
 Associated with androgenic hormones

5. Drug-Drug Interactions during
Metabolism
 Patients who routinely ingest barbiturates,
other sedative-hypnotics, or certain
antipsychotic drugs  require considerably
higher doses of warfarin to maintain a
therapeutic effect
 Discontinuance of the sedative inducer 
reduced metabolism of the anticoagulant and
bleeding – a toxic effect of the ensuing
enhanced plasma levels of the anticoagulant

6. Drug-Drug Interactions during
Metabolism
 An inducer may enhance not only the metabolism
of other drugs but also its own metabolism 
continued use of some drugs may result in a
pharmacokinetic type of tolerance
 Simultaneous administration of 2 or more drugs 
impaired elimination of its pharmacologic effects
 Competitive substrate inhibition and irreversible
substrate-mediated enzyme inactivation may
augment plasma drug levels and lead to toxic
effects from drugs with narrow therapeutic indices

7. Drug-Drug Interactions during
Metabolism
 Acute interactions of terfenadine with a CYP3A4
substrate-inhibitor  fatal arrhythmias
 Drug-drug interactions with CYP3A4 substrate
inhibitors, and consequent cardiotoxicity led to
withdrawal or restricted use of the 5-HT4
agonist, cisapride
 Cimetidine has been shown to potentiate the
pharmacologic actions of anticoagulants and
sedatives

8. Drug-Drug Interactions during
Metabolism
 The metabolism of the sedative chlordiazepam
has been shown to be inhibited by 63% after a
single dose of cimetidine
 Impaired metabolism may also result if a
simultaneously administered drug irreversibly
inactivates a common metabolizing enzyme
 Furanocoumarins in grapefruit juice inactivate
CYP3A4 in the intestinal mucosa and
consequently enhance proteolytic degradation

9. Interactions between Drugs and
Endogenous Compounds
 Some drugs require conjugation with
endogenous substrates for their inactivation
 Different drugs may compete for the same
endogenous substrates, and the faster-
reacting drug may effectively deplete
endogenous substrate levels and impair the
metabolism of the slower-reacting drug

10. Diseases Affecting Drug Metabolism
 Acute or chronic diseases that affect liver
architecture or function markedly affect hepatic
metabolism of some drugs
 alcoholic hepatitis
Active or inactive alcoholic cirrhosis
Hemochromatosis
Chronic active hepatitis
Biliary cirrhosis
Acute viral or drug-induced hepatitis

11. Diseases Affecting Drug Metabolism
 Depending on their severity, these conditions
may significantly impair hepatic drug-
metabolizing enzymes, particularly microsomal
oxidases
 Some drugs are metabolized so readily that
even marked reduction in liver function does
not significantly prolong their action
 However, cardiac disease, by limiting blood flow
to the liver, may impair disposition of those
drugs whose metabolism is flow-limited

12. Diseases Affecting Drug Metabolism

13. Diseases Affecting Drug Metabolism
 Pulmonary disease – may also affect drug
metabolism, as indicated buy the impaired
hydrolysis of procainamide and procaine in
patients with chronic respiratory insufficiency
and the increased half-life of antipyrine in
patients with lung cancer
 Endocrine dysfunction
Thyroid dysfunction
Hypothyroidism
hyperthyroidism

14. Diseases Affecting Drug Metabolism
 Malfunctions of the pituitary, adrenal cortex,
and gonads markedly reduce hepatic drug
metabolism in rats
 Diabetes – no apparent impairment of drug
metabolism, although impairment has been
noted in diabetic rats
 Release of inflammatory mediators, cytokines,
and nitric oxide associated with bacterial or
viral infections, cancer, or inflammation –
inactivating P450s and enhancing degradation

15. THANK
YOU!