L10 Metabolism Flashcards
where does drug metabolism primarily occur?
in the liver
what route of administration leads to greater bioavailability?
IV injection
what can happen to a drug during metabolism?
active to inactive
active to active or tocix
inactive to active (prodrug to drug)
unexcretable to excretable (increases elimination)
oxidation/reduction reactions occur mainly via?
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
what is involved in the metabolism of 75% of drugs?
CYP 450
what is the purpose of oxidation/reduction reactions?
to make metabolites more hydrophilic and increase solubility in urine - facilitate clearance
many drugs can be excreted after ___?
oxidation
what are the most common conjugate groups?
glucuronate and sulfate
where are conjugating enzymes mainly found?
in the liver
what may be a substrate for a conjugating enzyme?
drug
or drug metabolite (P450)
why are drugs conjugated?
so they can be secreted into bile
makes them more polar by attaching hydrophillic groups
what disorder is a result of deficient UDP-glucuronyl transferase?
kernicterus - high levels of unconjugated bilirubin (highly lipid soluble), crosses BBB
how do you treat kernicterus?
phototherapy - converts bilirubin to a form is more easily excreted.
where do multidrug resistance proteins 1 transport drug?
out of cell and back into GIT lumen
where do OAT and OCT transport drug?
into cytosol
what transports “statin” drugs into their site of action in hepatocytes?
OAT
responsible for renal secretion of many anionic drugs - NSAIDs and penicillins
___ can inhibit/induce expression of P450
drugs
what does inhibition of P450 prevent?
metabolism and clearance of drug
prodrugs are inactive until?
metabolized - allows us to be aware of the effects of toxic metabolites - which do nasty things
how is acetaminophen primarily metabolized?
conjugation/hydrolysis reaction (phase II) using glucuronidation and sulfation
under normal conditions, the NAPQI produced from acetaminophen metabolism reacts with ?
glutathione = conjugated intermediate = excreted
what happens with acetaminophen overdose?
not enough glutathione - NAPQI is toxic to liver! - give pt NAC to increase glutathione levels = antidote!
___ are important to how the pt will react to a drug
genetics
some drugs can acts a either ___ or ___ and inhibit P450
competitive or noncompetitive antagonists
what are the consequences of P450 induction?
- 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!
define pharmacokinetic tolerance
when a drug induces its own metabolism and thus reduces its efficacy over time
what diseases affect drug metabolism?
- liver disease - leads to decreased drug breakdown
- cardiac failure - leads to decrease drug delivery to liver
- hyperthyroidism - increases metabolism
