DDMetabolismExcretion Flashcards
Phase I enzyme action
Often P450. Usually inserts/unmasks a functional group [mostly -OH. Also -NH2 or -SH]. This increases water solubility and also allows Phase II RXN. Phase I RXNs include oxidation; reduction; hydrolysis.
Phase II enzyme action (conjugation)
Endogenous substrate combines with pre-existing or metabolically inserted functional group (via Phase I RXN). Forms a highly water-soluble conjugate that is readily excreted. Can also precede phase I RXNs
Most common Phase II RXNs?
Glucuronidation; acetylation; glutathione/glycine/sulfate conjugation
What is the most common pharmacologial consequences of drug metabolism?
Usually a detoxifying process (turns active drug to inactive or less active compound). Sometimes also can activate or turn the drug into a toxic metabolite
What are examples of active drugs that become further activated with metabolism?
Codeine to Morphine. Hydrocodone (vicadin) to hydromorphone (dilaudid)
What are examples of inactive drugs (prodrugs) that become the active ingredient (designed) with metabolism?
Omeprazole to a sulfenamide. Enalapril to enalaprilat. Valacyclovir to acyclovir
What is an example of a drug that gets converted to a toxic metabolite with metabolism?
Acetaminophen to N-acetyl-benzoquinoneimine (hepatotoxic)
What are the 4 types of metabolic RXNs?
Oxidations; Reductions; Hydrolysis (all Phase I). Conjugations (Phase II)
What group of enzymes does oxidations?
CYP450
What group of enzymes does hydrolysis?
Esterases-Amidases
What group of enzymes does reduction?
Reductases
What group of enzymes does conjugations?
Transferases
Where is most cytochrome P450?
Liver smooth ER (aka microsomal enzymes)
What else is part of the oxidation system that Cytochrome P450 is involved in?
The cofactor NADPH; the flavoprotein NADPH-cytochrome P450 reductase; and molecular O2.
Amplichip CYP450 Test
Analyzes blood DNA to detect genetic polymorphisms in the activity of CYP2D6 and CYP2C19. Note: clinical effect depends on whether metabolism is detoxifying or activating and whether polymorphism results in increased (UM-ultra metabolizer) or decreased (PM-poor metabolizer) enzyme activity
CYP3A4
Major drug metabolizing enzyme (found in gastric mucosa)
CYP2E1
Turns acetomenaphin into toxic metabolite
CYP2D6
Major metabolizers of opiod analgesics; antipsychotics; antidepressants. Genetic polymorphisms
What does CYP2D6 do to antipsychotics/antidepressants? What effects are there if you are PM? UM?
It detoxyfies. PMs see increased antipsychotic drug toxicity. Ums see nonresponse to antidepressants
What does CYP2C19 do to proton pump inhibitors (for peptic ulcer disease)? What effect is there if you are a PM?
It activates PPIs. PMs have decreased efficacy of PPIs
What effect does CYP2D6 do to codeine? What effect is seen with PMs? With UMs?
CYP2D6 activates codeine. PMs have insufficient analgesia with codeine due to failure to metabolize to morphine. UMs have condeine intoxication due to rapid metabolism to morphine
Which enzymes are more saturable/in limited supply (phase I or II enzymes)? Why?
Phase II enzymes in limited supply and RXN more easily saturable. B/C drug is conjugated to endogenous biochemical unit (highly reactive) provided by a coenzyme
Products of Phase II are usually�
highly water-soluble and readily excreted
Glucoronidation - type of enzymes
Glucoronyl transferases. Present in liver; kidney; GI tract. Inducible (but not to the extent as CYP450 enzymes)
Enterohepatic recirculation
Some intenstinal bacteria can hydrolyze the glucoronides (drug+conjugate from Phase II) and put the free drug back into circulation. Drug gets secreted by liver into bile as drug-conjugate and then bacteria in intestine cut the glucoronides. May be source of drug interactions (antibiotics and oral contraceptives)
Enzyme induction
Quantitative (or qualitative) increase in activity in response to certain compounds. Mainly due to increased synthesis of enzyme protein (decreased turnover also occurs). Generally requires 48-72 hrs to see onset
Is Phase I or Phase II more susceptible to induction?
Mostly CYP450 enzymes (some forms of phase II enzymes also).
What is induction/inhibition analagous to?
Poor metabolizers/ultra metabolizers. Both mostly effect Phase I. Clinical effects depend on whether metabolic RXN in inactivating or activating
Therapeutic consequences of induction
Sometimes see drugs having effects on their own metabolism. Also can have clinical implications of resulting drug interactions. (Reduced therapeutic effect if inactivation accelerated; increased toxicity if activation is accelerated; increased toxicity if toxic metabolite produced)
Clinically relevant inducers (7)
Phenobarbital; phenytoin; carbamazepine; rifampin; ethanol; St.John’s Wort; Tobacco smoke
Clinically relevant inhibitors (7)
Cimetidine; erythromycin/clarithromycin; azole antifungals; fluoxetine (other SSRIs); Grapefruit juice; HIV protease inhibitors; omeprazole
Is Phase I or Phase II more likely to be saturated?
Phase II
1st order kinetics vs. zero order kinetics
At low doses drug metabolism is 1st order (proportional to the drug dose. As dose goes up; so does rate of metabolism). At high doses drug metabolism is zero order (rate is constant and independent of the drug dose)
What most often causes zero order kinetics/saturation
Most often due to saturation of hepatic metabolic processes (phase II). Unlikely to occur with renal excretory processes
P-glycoproteins
Transports that play a role in elimination of things from cells (including drugs). AKA MDR1 gene - member of ABC family of transporters (ATP binding cassettes). When they remove things from cells at sites of entry (GI tract) they decrease absorption. At sites of exit (liver-kidney) they enhance elimination
What do inhibitors/inducers of p-glycoproteins do?
Inhibitors increase plamsa levels of drug substrates. Inducers decrease plasma levels
