Biliary transport of irinotecan and metabolites in normal and P-glycoprotein-deficient mice.

摘要: Purpose: The extensive and unpredictable biliary excretion of CPT-11 its metabolites, SN-38 glucuronide (SN-38G) may contribute to the wide interpatient variability reported in disposition gastrointestinal toxicity CPT-11. We studied role P-glycoprotein (P-gp) vivo CPT-11, SN-38G mice lacking mdr1-type P-gp [mdr1a/1b(–/–)] presence multidrug resistance (MDR) reversal agent, PSC833. Methods: Wild-type (Wt) mdr1a/1b(–/–) (n=3 or 4) were treated intragastrically with PSC833 (50 mg/kg) vehicle 2 h prior i.v. dosing (10 mg/kg), bile samples collected. Results conclusions: was found play an important excretion, as there a significant (40%, P<0.05) decrease recovery 90 min (6.6±0.6% dose) compared Wt (11±1.2%). This also implied major other undetermined non-P-gp-mediated mechanism(s) for hepatic transport which inhibited by (1.8±0.8% PSC833, 6.6±0.6% without PSC833) mice. unchanged after treatment, indicating lack mediation their transport. significantly reduced (56–89%) mice, suggesting that be candidate modulate potential use reducing toxicity.