L10 Metabolism

Question 1

where does drug metabolism primarily occur?

Answer 1

in the liver

Question 2

what route of administration leads to greater bioavailability?

Answer 2

IV injection

Question 3

what can happen to a drug during metabolism?

Answer 3

active to inactive
active to active or tocix
inactive to active (prodrug to drug)
unexcretable to excretable (increases elimination)

Question 4

oxidation/reduction reactions occur mainly via?

Answer 4

heme-protein oxidases

• CYP450
• microsomal mixed function oxidases
• bound to ER membrane
• mainly in liver
• involved in metabolism of 75% of drugs
• transform drug by adding OH or NH2 group

Question 5

what is involved in the metabolism of 75% of drugs?

Answer 5

CYP 450

Question 6

what is the purpose of oxidation/reduction reactions?

Answer 6

to make metabolites more hydrophilic and increase solubility in urine - facilitate clearance

Question 7

many drugs can be excreted after ___?

Answer 7

oxidation

Question 8

what are the most common conjugate groups?

Answer 8

glucuronate and sulfate

Question 9

where are conjugating enzymes mainly found?

Answer 9

in the liver

Question 10

what may be a substrate for a conjugating enzyme?

Answer 10

drug

or drug metabolite (P450)

Question 11

why are drugs conjugated?

Answer 11

so they can be secreted into bile

makes them more polar by attaching hydrophillic groups

Question 12

what disorder is a result of deficient UDP-glucuronyl transferase?

Answer 12

kernicterus - high levels of unconjugated bilirubin (highly lipid soluble), crosses BBB

Question 13

how do you treat kernicterus?

Answer 13

phototherapy - converts bilirubin to a form is more easily excreted.

Question 14

where do multidrug resistance proteins 1 transport drug?

Answer 14

out of cell and back into GIT lumen

Question 15

where do OAT and OCT transport drug?

Answer 15

into cytosol

Question 16

what transports “statin” drugs into their site of action in hepatocytes?

Answer 16

OAT

responsible for renal secretion of many anionic drugs - NSAIDs and penicillins

Question 17

___ can inhibit/induce expression of P450

Answer 17

drugs

Question 18

what does inhibition of P450 prevent?

Answer 18

metabolism and clearance of drug

Question 19

prodrugs are inactive until?

Answer 19

metabolized - allows us to be aware of the effects of toxic metabolites - which do nasty things

Question 20

how is acetaminophen primarily metabolized?

Answer 20

conjugation/hydrolysis reaction (phase II) using glucuronidation and sulfation

Question 21

under normal conditions, the NAPQI produced from acetaminophen metabolism reacts with ?

Answer 21

glutathione = conjugated intermediate = excreted

Question 22

what happens with acetaminophen overdose?

Answer 22

not enough glutathione - NAPQI is toxic to liver! - give pt NAC to increase glutathione levels = antidote!

Question 23

___ are important to how the pt will react to a drug

Answer 23

genetics

Question 24

some drugs can acts a either ___ or ___ and inhibit P450

Answer 24

competitive or noncompetitive antagonists

Question 25

what are the consequences of P450 induction?

Answer 25

• drug can increase its own metabolism = carbamazepine (anti-epileptic drug)
• drug can increase metabolism of co-administered drugs = rifampin and saquinavir!
• can produce toxic levels of reactive drug metabolites = tissue damage or side effects!

Question 26

define pharmacokinetic tolerance

Answer 26

when a drug induces its own metabolism and thus reduces its efficacy over time

Question 27

what diseases affect drug metabolism?

Answer 27

• liver disease - leads to decreased drug breakdown
• cardiac failure - leads to decrease drug delivery to liver
• hyperthyroidism - increases metabolism