Al-Mehdi: Drug Metabolism Flashcards
goal of phase 1 of liver detoxification
water solubility
drug activation
goal of phase 2 of liver detoxification
water solubility
drug inactivation
goal of phase 3 of liver detoxification
excretion into bile
therapeutic window of a drug is between what two thresholds
minimal effective concentration (MEC)
minimal toxic concentration (MTC)
grapefruit juice + simvastatin =
myopathy (toxicity)
St. John’s Wort + simvastatin =
drug ineffective (never reaches MEC)
CYP450s located where
smooth ER
what induces enzyme production
phenobarbitol
receptor for Rifampin that dimerizes and goes into nucleus and leads to CYP3A4 being produced and rifampin’s degradation
PXR
____ activated by CYP2C19
Clopidogrel
inhibits CYP2C19
Omeprazole
omeprazole + clopidogrel=
platelet aggregation
cimetidine + omeprazole =
bleeding
_____inactivates CYP2C9
Cimetidine
warfarin + cimetidine =
bleeding
____ inhibits CYP3A4
Erythromycin (macrolide)
Erythromycin + Warfarin =
bleeding
Erythromycin + Ketoconazole
long QT + long QT = Torsades de Pointes
Rifampin + oral contraceptives =
baby
main reaction used in phase 2 of liver detoxification
Glucuronidation (UDP, UGT1A1) for drug inactivation (and drug conjugation)
what happens when glucuronidation happens w/ phenytoin +/or bilirubin
conjugation (water solubility)
active form of IRINOTECAN
SN-38
inactive form of IRINOTECAN
SN-38 + glucuronic acid (inactivated by UGT1A1)
mutation in OATP1B1/P1B3
Rotor syndrome
no reuptake of conjugated bilirubin
blocks urate reabsorption in kidneys
blocks MRP2 (drugs not going into biliary space)
PROBENECID
used to treat irinotecan induced diarrhea
PROBENECID
transporter on apical side of hepatocyte that is found on many cells and cancer cells
MDR1
MRP2 mutation
Dubin-Johnson syndrome
transporter on apical side for Cu1+ (copper)
ATP7B
conjugated bilirubin exported through basolateral side through back through blood by _____
MRP3
____mutation leads to IRINOTECAN toxicity
UGT1A1
patient with Gilbert syndrome should not take _____ due to toxicity
IRINOTECAN
GEMFIBROZIL + SIMVASTATIN =
myoglobinuria
glucuronidation of bilirubin
double
UGT1A1 mutation (absence)
infants and children
kernicterus seen
type I Crigler-Najjar
UGT1A1 mutation (1-10% UGT1A1 activity)
infants and children
type II Crigler-Najjar
10-30% UGT1A1 activity
teens-30s
Gilbert syndrome
zone 3 necrosis seen with this drug induced toxicity
Acetaminophen
Rx acetaminophen toxicity
NAC
autoantibody causing fulminant hepatic necrosis w/ what drug induced toxicity
Halothane
mitochondrial injury from what drug induced toxicity
Valproic acid
drug induced toxicity leading to hepatic venous thrombosis
oral contraceptives
liver and brain injury due to previous virus and aspirin use
Reye syndrome
triad of fatty liver degeneration, elevated ALT/AST, and encephalopathy
Reye syndrome
hepatocyte mitochondrial dysfunction
elevated NH3
encephalopathy
Reye syndrome