Drug biotransformation Flashcards
Drugs excreted without modification
Small, polar, ionized at physiological pH (not reabsorbed)
Water soluble
Drugs modified for excretion
Lipid soluble, unionized, large compounds
Protein bound drugs
Terminate action and facilitate elimination
Consequences of biotransformation
Activate
Inactivate
Make more water soluble
Prodrug
Inactive drug that requires biotransformation to become an active drug
May have protective functional group
Main site of biostransformation
LIVER
First pass effect
Oral drugs are absorbed in SI and transported to liver where it goes through biotransformation
Greatly limits bioavailability
Some drug inactivated or activated in stomach due to acidity and GI (enzymes and GI flora)
Phase I Rxns
Inactivation
Redox, hydrolysis
p450s, FMO, mEH, sEH
Products generally more toxic and reactive
Phase II Rxns
Improve water solubility
Conjugation reactions
Faster rates to ensure efficient elimination
p450s
Contain heme
Use O2 and H+
CYP3A4 most abundant
p450 induction
Usually accelerate substrate metabolism and decrease action of inducer and coadministered drugs
Ex. ethanol, phenytoin, tobacco smoke, rifampin, barbiturates
Biotransformation enzyme inhibition
Competitive (antibiotics) or suicide (chloramphenichol) inhibition
Grapefruit - several classes of drugs
Allopurinol and mercaptopurine (chemo drugs)
Biotransformation genetic factors
Succinylcholine - some individuals metabolize at 50% rate
Slow acetylator - hepatotoxicity from TB drug, caffeine, hydralazine and other amines
Biotransformation in newborn
Enzyme function decreased
Hyperbilirubinemia
Poor BBB - increase risk of toxicity
Age related effect on biotransformation
Some overall decrease in liver and kidney function
Cardiac disease and elimination
Impair drugs whose elimination is flow dependent
