DDMetabolismExcretion

Question 1

Phase I enzyme action

Answer 1

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.

Question 2

Phase II enzyme action (conjugation)

Answer 2

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

Question 3

Most common Phase II RXNs?

Answer 3

Glucuronidation; acetylation; glutathione/glycine/sulfate conjugation

Question 4

What is the most common pharmacologial consequences of drug metabolism?

Answer 4

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

Question 5

What are examples of active drugs that become further activated with metabolism?

Answer 5

Codeine to Morphine. Hydrocodone (vicadin) to hydromorphone (dilaudid)

Question 6

What are examples of inactive drugs (prodrugs) that become the active ingredient (designed) with metabolism?

Answer 6

Omeprazole to a sulfenamide. Enalapril to enalaprilat. Valacyclovir to acyclovir

Question 7

What is an example of a drug that gets converted to a toxic metabolite with metabolism?

Answer 7

Acetaminophen to N-acetyl-benzoquinoneimine (hepatotoxic)

Question 8

What are the 4 types of metabolic RXNs?

Answer 8

Oxidations; Reductions; Hydrolysis (all Phase I). Conjugations (Phase II)

Question 9

What group of enzymes does oxidations?

Answer 9

CYP450

Question 10

What group of enzymes does hydrolysis?

Answer 10

Esterases-Amidases

Question 11

What group of enzymes does reduction?

Answer 11

Reductases

Question 12

What group of enzymes does conjugations?

Answer 12

Transferases

Question 13

Where is most cytochrome P450?

Answer 13

Liver smooth ER (aka microsomal enzymes)

Question 14

What else is part of the oxidation system that Cytochrome P450 is involved in?

Answer 14

The cofactor NADPH; the flavoprotein NADPH-cytochrome P450 reductase; and molecular O2.

Question 15

Amplichip CYP450 Test

Answer 15

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

Question 16

CYP3A4

Answer 16

Major drug metabolizing enzyme (found in gastric mucosa)

Question 17

CYP2E1

Answer 17

Turns acetomenaphin into toxic metabolite

Question 18

CYP2D6

Answer 18

Major metabolizers of opiod analgesics; antipsychotics; antidepressants. Genetic polymorphisms

Question 19

What does CYP2D6 do to antipsychotics/antidepressants? What effects are there if you are PM? UM?

Answer 19

It detoxyfies. PMs see increased antipsychotic drug toxicity. Ums see nonresponse to antidepressants

Question 20

What does CYP2C19 do to proton pump inhibitors (for peptic ulcer disease)? What effect is there if you are a PM?

Answer 20

It activates PPIs. PMs have decreased efficacy of PPIs

Question 21

What effect does CYP2D6 do to codeine? What effect is seen with PMs? With UMs?

Answer 21

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

Question 22

Which enzymes are more saturable/in limited supply (phase I or II enzymes)? Why?

Answer 22

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

Question 23

Products of Phase II are usually�

Answer 23

highly water-soluble and readily excreted

Question 24

Glucoronidation - type of enzymes

Answer 24

Glucoronyl transferases. Present in liver; kidney; GI tract. Inducible (but not to the extent as CYP450 enzymes)

Question 25

Enterohepatic recirculation

Answer 25

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)

Question 26

Enzyme induction

Answer 26

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

Question 27

Is Phase I or Phase II more susceptible to induction?

Answer 27

Mostly CYP450 enzymes (some forms of phase II enzymes also).

Question 28

What is induction/inhibition analagous to?

Answer 28

Poor metabolizers/ultra metabolizers. Both mostly effect Phase I. Clinical effects depend on whether metabolic RXN in inactivating or activating

Question 29

Therapeutic consequences of induction

Answer 29

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)

Question 30

Clinically relevant inducers (7)

Answer 30

Phenobarbital; phenytoin; carbamazepine; rifampin; ethanol; St.John’s Wort; Tobacco smoke

Question 31

Clinically relevant inhibitors (7)

Answer 31

Cimetidine; erythromycin/clarithromycin; azole antifungals; fluoxetine (other SSRIs); Grapefruit juice; HIV protease inhibitors; omeprazole

Question 32

Is Phase I or Phase II more likely to be saturated?

Answer 32

Phase II

Question 33

1st order kinetics vs. zero order kinetics

Answer 33

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)

Question 34

What most often causes zero order kinetics/saturation

Answer 34

Most often due to saturation of hepatic metabolic processes (phase II). Unlikely to occur with renal excretory processes

Question 35

P-glycoproteins

Answer 35

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

Question 36

What do inhibitors/inducers of p-glycoproteins do?

Answer 36

Inhibitors increase plamsa levels of drug substrates. Inducers decrease plasma levels