3 Flashcards
(10 cards)
Give an example of a Phase 2 conjugation that does not require prior activation (Phase 1).
Glutathione conjugation (via glutathione S-transferase) of electrophilic substrates does not require prior functionalization.
How does rifampicin’s induction of CYP450 affect its own metabolism over time?
As rifampicin induces the enzymes that metabolize it, its own clearance increases, potentially leading to the need for dose adjustments with chronic use.
What role do bile salt transporters play in enterohepatic circulation?
Bile salt transporters (e.g., OATs) concentrate hydrophilic drug conjugates into bile; bacterial enzymes in the gut can hydrolyze them, releasing the parent drug for reabsorption.
Why is morphine’s pharmacokinetic profile influenced by enterohepatic circulation?
Morphine–glucuronide conjugates excreted in bile can be hydrolyzed in the intestine to free morphine, which is reabsorbed, prolonging its effect.
Describe one way co-administration of two drugs can alter renal excretion of one.
If Drug A displaces Drug B from plasma proteins, free Drug B increases, leading to higher glomerular filtration and faster elimination; alternatively, Drug A might inhibit tubular secretion of Drug B, slowing its clearance.
What is the clinical significance of polymorphisms in ethanol-metabolizing enzymes?
Certain populations (e.g., some East Asians) have reduced alcohol dehydrogenase or aldehyde dehydrogenase activity, leading to acetaldehyde buildup, flushing, and increased intoxication risk.
How can a drug interaction lead to an ‘apparent’ change in half-life without altering metabolism?
If one drug displaces another from tissue binding sites or plasma proteins, the volume of distribution changes, altering the apparent half-life even if metabolic clearance is unchanged.
Why might a patient with hepatic cirrhosis require dose adjustment of highly metabolized drugs?
Cirrhosis reduces functional hepatic mass and blood flow, decreasing metabolic capacity and increasing drug exposure, necessitating lower or less frequent dosing.
What is the impact of impaired renal function on Phase 2 conjugate excretion?
Conjugated metabolites that rely on renal elimination accumulate, potentially causing adverse effects; dose reduction may be needed.
How does the presence of a handle (e.g., –OH, –NH₂, –SH) on a drug molecule influence its susceptibility to Phase 2 conjugation?
The handle provides a site for conjugating enzymes (UGTs, sulfotransferases, GSTs, etc.) to attach polar groups, facilitating water solubility and excretion.
