The effect of P-glycoprotein and cytochrome P450 3a on the oral bioavailability of vinorelbine in mice.
OBJECTIVE
This study was designed to determine the effects of P-glycoprotein (P-gp) and cytochrome P450 3a metabolism on the oral bioavailability of the vinca alkaloid Vinorelbine (Navelbine; VRL).


METHODS
Pharmacokinetics of VRL were determined in FVB wild-type and mdr1a/1b (-/-) mice after oral and intravenous administration of 10 mg/kg VRL with or without oral ritonavir (5 mg/kg) prior to VRL. Serial blood samples were drawn for a period of up to 48 hours using mice with a cannulated jugular vein. Feces was collected for a period of 96 hours. VRL was determined by ion-exchange HPLC in combination with fluorescence detection.


RESULTS
The oral bioavailability in wild-type was 16.0+/-1.4% (mean+/-SE) and was not significantly higher in mdr1a/1b (-/-) mice (17.9+/-0.7%). Both after intravenous and oral administration, the AUC was not significantly different between wild-type and mdr1a/1b(-/-) mice. When RTV was co-administered the AUC of intravenous VRL increased significantly by 30% (p = 0.012). Because RTV increased the AUC of oral VRL by 83% the oral bioavailability was increased to 22.5+/-2.3% (p = 0.016). The fecal recovery of unchanged VRL was about 34 and 6% of the dose in wild-type and mdr1a/1b(-/-) mice, respectively, and was not altered by RTV.


CONCLUSIONS
This study shows that P-gp has little effect on the disposition and oral bioavailability of VRL. A substantial fraction of an oral dose of VRL is absorbed from the gut of wild-type mice. Consequently, first-pass metabolism is the most important factor for explaining the modest oral bioavailability, but the results with RTV suggest that cyp3a plays only a modest role in metabolic breakdown in mice. Apparently, other routes of metabolic elimination are more important. These results suggest that also in patients the oral bioavailability may not gain substantially from the co-administration of a potent P-gp and/or Cyp3a inhibitor.
Press
Rogier R
RR
Department of Clinical Chemistry, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
Buckle
Tessa
T
Beijnen
Jos H
JH
van Tellingen
Olaf
O
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000077235:Vinorelbine; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D051544:Cytochrome P-450 CYP3A; D014747:Vinblastine; D000077235:Vinorelbine; D000097202:ATP-Binding Cassette Sub-Family B Member 4