Human OATP1B1, OATP1B3 and OATP1A2 can mediate the in vivo uptake and clearance of docetaxel.
Organic anion transporting polypeptides (human: OATPs and mouse: Oatps) are uptake transporters with important roles in drug pharmacokinetics and toxicity. We aimed to study the in vivo impact of mouse and human OATP1A/1B transporters on docetaxel plasma clearance and liver and intestinal uptake. Docetaxel was administered to Oatp1a/1b knockout and liver-specific humanized OATP1B1, OATP1B3 and OATP1A2 transgenic mice. Experiments were conducted with a low polysorbate 80 (2.8%) formulation, as 8% polysorbate somewhat inhibited docetaxel plasma clearance after intravenous administration. After intravenous administration (10 mg/kg), Oatp1a/1b knockout mice had an approximately threefold higher plasma area under the curve (AUC). Impaired liver uptake was evident from the significantly reduced (approximately threefold) liver-to-plasma AUC ratios. Absence of mouse Oatp1a/1b transporters did not affect the intestinal absorption of orally administered docetaxel (10 mg/kg), while the systemic exposure of docetaxel was again substantially increased owing to impaired liver uptake. Most importantly, liver-specific expression of each of the human OATP1B1, OATP1B3 and OATP1A2 transporters provided a nearly complete rescue of the increased plasma levels of docetaxel in Oatp1a/1b-null mice after intravenous administration. Our data show that one or more of the mouse Oatp1a/1b transporters and each of the human OATP1A/1B transporters can mediate docetaxel uptake in vivo. This might be clinically relevant for OATP1A/1B-mediated tumor uptake of docetaxel and for docetaxel clearance in patients in whom the transport activity of OATP1A/1B transporters is reduced owing to genetic variation or pharmacological inhibition, leading to potentially altered toxicity and therapeutic efficacy of this drug.
Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Dilek
D
Iusuf
Jeroen J M A
JJ
Hendrikx
Anita
A
van Esch
Evita
E
van de Steeg
Els
E
Wagenaar
Hilde
H
Rosing
Jos H
JH
Beijnen
Alfred H
AH
Schinkel
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D001692:Biological Transport; D002626:Chemistry, Pharmaceutical; D000077143:Docetaxel; D005816:Genetic Complementation Test; D006801:Humans; D007408:Intestinal Absorption; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000502:physiology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000502:physiology*; D011136:Polysorbates / Q000008:administration & dosage; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D043823:Taxoids / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011136:Polysorbates; C512988:SLCO1A2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D043823:Taxoids; D000077143:Docetaxel
OATP1A/1B; OATP1B1; OATP1B3; docetaxel; organic anion transporting polypeptides (OATPs)