title: Low systemic exposure of oral docetaxel in mice resulting from extensive first-pass metabolism is boosted by ritonavir.
abstract: P-glycoprotein seems to be the most important factor limiting the oral absorption of paclitaxel. We have now explored the mechanisms responsible for the low oral bioavailability of docetaxel, a structurally related taxane drug. The recovery of 33% of oxidative metabolites and only 39% of unchanged drug in the feces of FVB wild-type mice receiving 10 mg/kg of oral docetaxel indicates that the major part of the oral dose has been absorbed. The feces and bile of mice receiving 10 mg/kg of i.v. docetaxel contained large amounts of metabolites and only minor quantities of unchanged drug, highlighting the importance of metabolism as an elimination route for this drug. In wild-type and P-glycoprotein knockout mice, dose escalation of p.o. administered docetaxel from 10 to 30 mg/kg resulted in a more than proportional increase in plasma levels, which suggested saturation of first-pass metabolism. Moreover, coadministration of 12.5 mg/kg of the HIV protease inhibitor ritonavir, also a strong inhibitor of cytochrome P4503A4 with only minor P-glycoprotein inhibiting properties, increased the plasma levels after oral docetaxel by 50-fold. In vitro transport studies across monolayers of LLC-PK1 cells (parental and transduced with MDR1 or Mdr1a) suggested that docetaxel is a weaker substrate for P-glycoprotein than paclitaxel is. In conclusion, docetaxel is well absorbed from the gut lumen in mice despite the presence of P-glycoprotein in the gut wall. Subsequent first-pass extraction is the most important factor determining its low bioavailability. The inhibition of docetaxel metabolism by ritonavir provides an interesting strategy to improve the systemic exposure of oral docetaxel.
authors.affiliation: The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam.
authors.forename: Heleen A
authors.initials: HA
authors.lastname: Bardelmeijer
authors.forename: Mariët
authors.initials: M
authors.lastname: Ouwehand
authors.forename: Tessa
authors.initials: T
authors.lastname: Buckle
authors.forename: Maarten T
authors.initials: MT
authors.lastname: Huisman
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000494:pharmacology*; D043823:Taxoids
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; C095122:multidrug resistance protein 3; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir; D017239:Paclitaxel