Human OATP1B1, OATP1B3 and OATP1A2 can mediate thein vivouptake and clearance of docetaxel

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Abstract

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.

What's new?

Proteins of the organic anion-transporting polypeptide (OATP) superfamily serve major roles in drug transport, potentially influencing drug distribution, action, and toxicity. In the case of the anticancer agent docetaxel, transporters OATP1B1 and OATP1B3, which are expressed in tumors, may affect hepatic clearance and systemic exposure, according to the present study. Liver uptake of docetaxel was found to be impaired in Oatp1a/1b knockout mice, leading to significant increases in drug plasma levels. Plasma levels were reduced with liver-specific expression of human OATP1A/1B transporters. Reduced transporter activity, through genetic variation or pharmacological inhibition, could alter the therapeutic index of docetaxel.

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