Drug Biotransformation Flashcards
xenobiotics
foreign substances within the body
what drugs are very much in need of biotransformation
lipophilic
unionized
large compounds
to terminate and faciliate their elimination
what is a prodrug
inactive to active
where are the important sites of biotransformation
liver
GI tract, lungs, skin and kidneys
where are enzymes located involved in biotransformation
ER mitochondria cytosol lysosomes nuclear envelope plasma membrane
what is first pass
oral drugs are absorbed in the small intestine and transported to the liver via hepatic portal system where they undergo extensive metabolism
drugs that are given parenterally DO NOT undergo first pass
what does GI flora do to estrogens
increase enterohepatic cycling thereby increasing bioavailability
that is why antimicrobial drugs reduce estrogen efficacy
what do phase I rxns result in
biological inactivation
what do phase II rxns result in
metabolite with improved water solubility and increased molecular weight -> facilitates elimination
phase 1 rxns
enzymes?
types of rxns…
catabolic
convert parent drug to more polar metabolite by introducing or unmasking a functional group
oxidation, reduction, hydrolysis
cytochrome P450’s
phase 1 produces are generally more what… compared to parent drug
more reactive and more toxic
where are phase 1 enzymes located
lipophilic ER membranes of liver
phase II reactions
rxns
form a conjugate of the parent drug
conjugate is polar and large inactive
occurs faster than phase I
usually happens in the liver
what are the most important CYP’s (P450’s)
CYP1A2 CYP2A6 CYP2D6 CYP2E1 CYP3A4***
how do P450’s work
use O2 and H+ derived from the cofactor-reduced NADPH to carry out oxidation –> add one oxygen atom per drug molecule which makes it more water soluble (polar)
individuals with a genetic defect in pseudocholiesterase can do what…
metabolize succinylcholine at 50% the rate as normal individuals
succ–> depolarizing neuromuscular blocking drug
so in the ER if a patient is not responding to succ, then consider genetic defect
what is the slow acetylator phenotype
autosomal recessive
have a DECREASE in N-acetyltransferase levels (rather than a mutated enzyme) in the liver
so when given isoniazid to treat TB, hydralazine (to treat HTN) or caffeine, these are metabolized at a slower rate
can lead to hepatotoxicity !! hepatitis
occurs in 50% US population
83% of French
less in Asians
what are examples of inducers of P450?
phenytoin - anticonvulsant chronic ethanol (CYP2E1) aromatic hydrocarbons like benzoapyrene (tobacco) rifampin (anti-TB) phenobarbital- anesthesia
what is the effect of P450 inducers
enhance the rate of enzyme synthesis or reduce the rate of enzyme degradation
leads to acceleration of substrate metabolism
what effect does grapefruit juice have?
irreversibly inhibit intestinal CYP3A4 –> leads to increased levels of drugs taken orally
what is the relationship b/w allopurinol and mercaptopurine
allopurinol is used for gout treatment
allopurinol inhibits xanthine oxidase
xanthine oxidase is a key enzyme in biotrasnfomring the immunosuppressive agent mercaptopurine (used during cancer treatment)
coadministration of mercaptopurine and allopurinol –> prolongs the duration of mercaptopurine action –> enhances its effects (both chemotherapeutically and toxically)
doses of mercaptopurine must be reduced in patients receiving allopurinol
why does hyperbilirubinemia occur in the newborn
metabolism of fetal hemoglobin –> bilirubin levels rise and accumulate in blood
newborns have immature hepatic metabolic pathways and are unable to conjugate bili with UDP glucuronic acid so they can’t excrete bili
what is a classic example of biotransformation to more toxic products
acetaminophen - induced hepatotoxicity
when acetaminophen exceeds therapeutic dose –> hepatic GSH is depleted faster than it is regenerated
toxic metabolites accumulate–> hepatotoxicity
