8/8/16 Drug Metabolism, Pharmacogenetics, Therapeutic Choice - Pilch Flashcards
routes of elimination:
renal elimination
excretion through kidney UNCHANGED
- esp useful for small sized and/or polar molecules
- flipside: many drugs are lipophilic, so kidneys arent best → lipophilic molecules can be reabs’d through tubular membranes
how does the body get rid of lipophilic compounds like drugs?
routes of elimination:
biotransformation aka metabolism
how?
chemical alteration (usually nonpolar/hydrophilic → polar/hydrophilic)
transformation of drugs and xenobiotics into more polar metabolites to make them more readily excretable
how? via enzymes evolved to handle xenobiotics, foreign agents/toxins
endogenous enzymatic systems evolved for handling xenobiotics catalyze most drug metab rxns
drug metabolism affects…
- pharmacodynamics
- pharmacokinetics
- toxicity
pharmacodynamics
- metabolic products can be inactive or more active (depending on drug and how it’s altered)
pharmacokinetics
- typically reduced half-life & higher clearance
toxicity
- usually detoxes (although some metabolites have higher tox - ex. acetominophen)
therapeutic choice
physicians need to know the factors that impact the metabolism of prescribed drugs (esp those with narrow therapeutic index)
- balance to ensure that metab is fast enough to avoid toxicity, slow enough to reach effective concentration
drug metabolism rxns
phase I : functionalization - expose or add a polar fx group to the parent compound
- phase I enzymes mediate
phase II : conjugation - attachment of endogenous compounds (glucuronic acid, glutathione, etc) to phase I products to yield polar conjugates (chem. inactive)
- phase II enzymes mediate
lipophilic → hydrophilic
sites of drug metabolism
primary player: LIVER
-
first pass effect: highly metabolized drugs don’t work well through oral administration
- once digested, drug is absorbed and pumped into portal circulation, where liver goes to work
- net effect: drug never makes it to the target because it is metabolized and excreted so quickly
- (oral) bioavailability: how much is available when taken orally
other drug metabolizers: lungs, kidneys, skin, GI tract (microorgs, digestive enzymes, gastric fluids)
phase I rxns
- aka…
- mediated by
- functionalization (oxidative) rxn
- mediated by cytochrome P450 (CYP)-dependent oxidation system
CYPs
- low substrate specificity (common feature of substrates: high lipid solubility)
- sluggish catalysts with slow biotransf rxn rates
CYP gene classification
based on aa sequence similarity:
- 18 families (<40%)
- 43 subfamilies (40-70%)
- 57 individ genes
numeral - letter - numeral
ex. CYP3A4
key CYPs
- how only 6?
- which is most imp?
- 3A4***
- 2C9*
- 1A2
- 2E1
- 2D6**
- 2C19*
responsible for bulk of drug/xenobiotic metabolism in liver
CYP3A4 accounts for metabolism of over 50% of drugs undergoing hepatic metab
phase II rxns
aka…
enzyme involved
types of rxns
conjugation rxns
- mediated by transferases
- conjugates tend to be highly polar → promotes elimination in urine/bile!
conj rxns include…
-
glucuronidation
- [UDP-glucuronysyltransferase] UGT
- methylation
- [thiopurine methyltransferase] TPMT
-
glutathione conjugation
- conjugation of reactive electrophilic compounds with tripeptide glutathione
- key for detox of drugs/carcinogens
- [glutathione-S-transferase] GST
- sulfation
- [sulfotransferase] ST
- N-acetylation
- [N-acetyltransferase] NAT
drug metabolism ex.
isoniazid
INH is an exception to sequential metabolism rxns
toxic drug
- phase II acetylation
- phase I hydrolysis
* yields acetylhydrazine, which is hepatotoxic
drug metabolism ex.
acetominophen
- routes of metabolism, which one is bad, antidote
three possible fates: Ac → …
- most → Ac-Glucuronide (phase 2)
- some → Ac-sulfate (phase 2)
- even less → Ac* (reactive electrophilic compound via phase 1 CYP450 hydroxylation)
Ac* is highly reactive, can either wreak havoc as an ROS or be neutralized&excreted
1. wreak havoc: conjugates with proteins → Ac*-protein →→ hepatic cell death
2. excreted: conjugates with GSH → GS-Ac* →→ Ac-mercapturate (excreted in urine)
antidotes: cysteamine, N-acetylcysteine
factors affecting drug metabolism
- genetic factors
- genetic defects, polymorphisms → inter-individ diffs in drug metabolic rates!
- non-genetic factors
- age/gender
- disease
- environmental determinants
- dietary, environmental, drug-drug interactions, drug-endog_compound interactions
metabolism of INH as ex. of genetic variation effect on drug metabolism
noticed that some people who were given INH would just have increasing levels of it in their systems → massive liver damage
- turned out to be due to polymorphism of NAT2 gene (N-acetyltransferase 2)
- homo slow individ presents like a drug OD
recommendation? lower dose, decrease frequency, or both
dietary/herbal/environmental factors leading to…
- induction
- inhibition
induction : increasing amount of CYP enzymes
- charcoal-broiled food : 1A
- cruciferous veg: 1A
- cig smoking: 1A, 2E
- chronic alc cons: 2E
- St. John’s Wort***: 3A
- [bad! why? 3A is a bigtime player]
inhibition : decrease activity of CYPs
- grapefruit juice: 3A4
