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

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