Drug Metabolism Flashcards
What organs function in drug metabolism? (4)
- Liver 20-30%
- kidney 8%
- intestine 6%
- skin 1%
What 4 factors influence drug membrane passage?
- Size (smaller better)
- Lipid solubility
- Degree of ionization (unionized form better)
- concentration gradient
Drug metabolism commonly converts drugs to larger more _____ and ______ compounds that are easily excreted
hydrophilic, ionized
What drugs are metabolized to more active compounds?
Codeine -> Morphine
Hydrocodone -> Hydromorphone
What drugs are metabolized from inactive prodrug to active drug?
Omeprazole -> a sulfenamide
Enalapril -> enalaprilat
Valacyclovir -> acyclovir
What drug is metabolized to a toxic metabolite?
acetaminophen -> N-Acetyl-benzoquinoneime (hepatotoxic)
_______ inserts or unmasks a functional group on the drug that renders the molecule more water soluble
Phase I
Name the 3 reactions in phase 1
oxidation, reduction, hydrolysis
Describe components of the phase 1 oxidation system (4)
enzyme CYP450 (liver is the richest source)
cofactor NADPH
Flavoprotein NADPH-cytochrome P450 reductase
molecular O2
Phase 1 oxidations (P450) are unlikely/likely to display zero order kinetics?
zero order kinetics = saturation kinetics, this is unlikely in phase 1 oxidation because cofactors are in abundant supply
CYP450 Dependent Oxidations (3)
Aromatic hydroxylations
Aliphatic hydroxylations
Oxidative dealkylation
CYP450 Independent Oxidations
Monoamine oxidase
Alcohol dehydrogenase
Aldehyde dehydrogenase
2 types of phase I hydrolysis
- Esterases - Ester local anesthetics, utilized in design of prodrugs (valacyclovir), Procaine metabolized to allergenic PABA
- Amidases - amide local anesthetics
Where are Esterases and Amidases primarily found?
Esterases - plasma, liver, other sites
Amidases - primarily liver and gut, less in plasma
3 less common phase I reductions
Reductases:
1. Azo reduction (sulfonamides)
2. Nitro reduction (chloramphenicol, toxic intermediates)
3. Carbonyl reduction (methadone)
“Substrates are high-energy and in limited supply, increased likelihood of depletion and zero order kinetics” What phase is this?
Phase II conjugations
What enzymes and reactions are involved in phase II conjugation?
Enzyme - transferases
Reactions: Glucuronidation, acetylation, glutathione/glycine/sulfate conjugation
Phase II conjugation forms highly ____ conjugate that is readily excreted via the urine
polar (water soluble)
Describe what happens in phase II?
endogenous substrate combines with pre-existing or metabolically inserted functional group (from phase I) on the drug
_______ reach adult values within the first few months
esterases
________ _________ are microsomal enzymes in the liver, kidney, and GI tract, adult levels of activity reached by age 3-4
Glucuronyl transferases
How are drugs excreted after glucuronidation?
Conjugates that are highly water soluble excreted via urine. Higher MW conjugates excreted in bile then feces.
What does hydrolysis by bacterial b-glucuronidase result in?
free drug in the intestine can be reabsorbed and reenter circulation, enterohepatic recirculation may be a source of drug interactions (antibiotics & OCs)
___________ form amide bond with amino group of drug, acetyl group in donated by acetyl CoA
N-acetyltransferases
______ activity can display marked genetic variation in humans
acetylation,
50% fast 50% slow acetylators in metabolism of isoniazid (TB drug)
Certain _________ from N-acetylation are less water soluble
Sulfonamides
What is the enzyme and coenzyme in sulfate conjugation?
Sulfotransferases, coenzyme PAPS
Describe sulfate conjugates (Phase II conjugation)
sulfate conjugates are ionized and water-soluble acids with a pKa of 1
Glutathione conjugation via glutathione S transferases is extremely important in what process?
detoxification of carcinogens, pollutants, and toxic metabolites (e.g. acetaminophen)
What is the toxic compound produced in acetaminophen metabolism? What is the treatment for overdose?
Toxin - reactive electrophilic compound AC produced by P450
Treatment - N-acetylcysteine inactivates AC directly
What test determines polymorphisms in CYP2D6/ 2C19?
amplichip test
CYP2D6 is involved in metabolism of what?
antipsychotic drugs, antidepressants, codeine/analgesics
CYP2C19 is involved in metabolism of what?
Proton pump inhibitors (PPI) for peptic ulcer disease (PUD)
5-10% of Caucasians are poor metabolizers of _____
20% of Asians are poor metabolizers of ____
CYP2D6
CYP2C19
When are effects of enzyme induction and inhibition most obvious?
When drugs are given orally via 1st pass effect
What is the clinical effect of induction and inhibition dependent on?
Whether the metabolic reaction is inactivating/detoxifying (95%), activating (5%), or produces a toxic metabolite
Name the 7 inducers
PPCREST
Phenobarbital
Phenytoin
Carbamazepine
Rifampin
Ethanol
St. Johns Wart
Tobacco Smoke
Name the 7 inhibitors
HOGFACE
HIV protease inhibitors
Omeprozole
Grapefruit juice
Fluoxetine
Azole antifungals
Cimetidine
Erythromycin
Induction of drug metabolism generally takes ________ hrs to see onset of effect
48-72 hrs
Which enzymes are more prone to inhibition? (phase I or phase II)
Phase I
When can onset of inhibition occur?
When effective levels in the liver are reaches, within hours
What mechanisms cause inhibition?
an inhibitor can be a substrate competing for an enzyme, a compound inhibiting the synthesis of enzyme, or and allosteric inhibitor (not directly competing at active site)
Byproducts of methanol metabolism cause an accumulation of ____ in the blood, ______, and death.
acid, blindness
What is the treatment for methanol-ethylene glycol poisoning?
ethanol, inhibits the enzyme that produces formic acid
How does age affect drug metabolism?
Perinatal - some enzymes not well developed at birth
Neonates - variable development patterns
Old age - decrease in phase 1 CYP450 in 1/3
What is thought to cause decrease in phase 1 CYP450 with aging?
decrease in hepatic blood flow
Why are phase II enzymes unlikely to decrease with aging?
transferases in other tissues can compensate
What conditions may require dosage adjustments or drug avoidance?
hepatic diseases, conditions affecting liver blood flow, non-hepatic diseases, alcohol consumption
What is zero order kinetics compared to first order kinetics?
In first order kinetics drug metabolism is proportional to drug dose, zero order kinetics is where a constant amount of drug is eliminated per unit time and is independent of drug dose
What causes zero order kinetics?
Saturation of hepatic metabolic processes (esp. phase II conjugations), seen with few drugs at therapeutic doses and many drugs at toxic doses
