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


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.
Iyer
Lalitha
L
Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC 2115, Chicago, IL 60637, USA. lalitha.iyer@sri.com
Ramírez
Jacqueline
J
Shepard
Dale R
DR
Bingham
Christopher M
CM
Hossfeld
Dieter-Kurt
DK
Ratain
Mark J
MJ
Mayer
Ulrich
U
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D000077146:Irinotecan; D051379:Mice
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D000077146:Irinotecan; D002166:Camptothecin