Drug Metabolism, Pharmacogenetics, and Therapeutic Choice (Pilch) - 080916 Flashcards
What are the two major routes through which drugs are eliminated from the body?
- Excreted through KIDNEY UNCHANGED
* However, excretion is poor b/c most drugs are LIPOPHILIC which allows them to pass through membranes and be reabsorbed - BIOTRANSFORMATION OF DRUGS (via chemical rxns) OR XENOBIOTICS (foreign compounds) into more polar, hydrophilic metabolites
Why is the metabolism of drugs into more hydrophilic metabolites critical for termination of biological activity and elimination from the body?
- It alters the PHARMACODYNAMIC properties of drugs
- Most metabolic products are inactive or less active than parent drugs
- Some metabolic products may have enhanced activity (e.g., inactive pro-drugs may be converted to active drugs metabolically) - It alters the PHARMACOKINETIC properties of drugs
- Typically inc. clearance and shortens 1/2 lives to significant extents (example: 1/2 of lipophilic barbiturates would be extremely long if it were not for their metabolic conversion to water soluble compounds) - It affects the TOXIC properties of drugs
- Usually detoxifies, although some metabolic products have enhanced toxicity relative to parent drug (e.g., acetaminophen)
Drug metabolism reactions occur at some point between absorption into circulation and renal elimination. Describe Phase I and Phase II reactions.
Phase I reactions = functionalization
*introduce or expose a polar functional group (e.g., OH, COOH, NH2, or SH) on the parent compound.
Phase II reactions = conjugation
*Involve conjugation of endogenous compounds (e.g., glucuronic acid or glutathione) to phase I products –> RESULT: highly polar (chemically inactive) conjugates
Phase I enzymes catalyze phase I rxns;
Phase II enzymes catalyze phase II rxns
Where does drug metabolism occur and what is the first-pass effect?
LIVER
First-pass effect:
Oral –> transported via portal system to liver (undergo extensive metabolism) –> systemic circulation
Limits oral bioavailability of highly metabolized drugs
Major enzyme for Phase I functionalization (oxidative) reactions?
CYP 450 - sluggish catalysts
Promiscuous enzymes, with low substrate specificity (bind anything)
CYP3A4 = accounts for the metabolism of >50% of the clinically prescribed drugs that undergo hepatic metabolism
Major enzyme for Phase II conjugation reactions
Transferases catalyze transfer of a really polar conjugate from its endogenous place to the drug
Highly polar nature of most conjugates promotes their elimination in urine or bile
Conjugation reactions include:
- Glucuronidation (transfer glucuronic acid)***
- N-acetylation (transfer acetyl group onto nitrogen)
- Glutathione conjugation*** (major detox pathway for drugs and carcinogens)
- Sulfation
- Methylation
Why is Isoniazid (INH) an exception to the sequential drug metabolism pattern?
INH –> Phase II (acetylation) –> Phase I (hydrolysis) –> Isonicotinic acid + acetylhydrazine [hepatotoxicity]
Describe the metabolism reactions of acetaminophen (tylenol).
Slide 18
Factors affecting drug metabolism:
Genetic factors
- Genetic defects
- Genetic polymorphisms
Non-genetic factors
- Age and gender
- Disease (esp. liver disease)
Environmental determinants:
- Dietary factors: cigarette smoking, alcohol consumption
- Environmental factors: pollutants, pesticides
- Drug-drug interactions: inhibition or induction of drug metabolism
- Drug interactions w/ endogenous compounds
Genetic factors contribute to large inter-individual differences in metabolic rate
Example: N-acetylation of isoniazid
Polymorphism of NAT2 (N-acetyltransferase 2) gene
Patients with 2 alleles of “slow” NAT2 exhibit slower acetylator phenotype
Adverse response resembles a drug overdose (emphasizing importance of ID-ing a polymorphism of NAT2 gene)
Recommendation? Reduce dosage or increase dosing interval
Dietary, herbal, and environmental factors in drug metabolism
Induction (increasing the amount of CYP enzymes):
Inhibition (inhibiting the activity of CYP enzymes):
Induction - induce CYP genes and increase metabolism rates of some drugs
- Charcoal-broiled foods (CYP1A)
- Cruciferous vegetables (CYP1A)
- Cigarette smoking (CYP1A and CYP2E)
- Chronic alcohol consumption (CYP2E)
- St. John’s Wort (CYP3A)
Inhibition - inhibiting activity of CYP enzymes and decrease metabolism rates
- Grapefruit juice (CYP3A4)
Drug-drug interactions
Slide 23
Effect of disease on drug metabolism
- Acute and chronic diseases that affect liver function or markedly diminish the metabolism of some drugs
- Cardiac disease
- Heavy metal poisoning and porphyria
Acute and chronic diseases that affect liver function or markedly diminish the metabolism of some drugs
- Alcoholic or Viral-induced hepatitis
- Alcoholic or biliary cirrhosis
- Cancer (e.g., hepatocarcinomas)
Cardiac disease
- Limit blood flow to the liver and impair disposition of drugs (e.g., morphine and lidocaine) whose metabolism is flow-limited
Heavy metal poisoning and porphyria (heme production in liver is defective)
- Impair hepatic drug metabolism by impairing activity or causing defective formation of metabolic enzymes
Effect of age and gender on drug metabolism
Very young/very old patients exhibit increased susceptibility to drug activities (both pharmacologic and toxic) compared w/ young adults
Phase I and II rxns occur in newborns, but generally at slower rate than adults
Age related decreases in liver mass, hepatic enzyme activity, and hepatic blood flow decrease overall metabolic activity (particularly CYP) in elderly
Pregnancy induces certain metabolizing enzymes in second and third trimesters - adjust dosage accordingly
Some oral contraceptive agents are potent irreversible inhibitors of CYP enzymes
