High Impact of Oatp1a/1b Transporters on In Vivo Disposition of the Hydrophobic Anticancer Drug Paclitaxel

Abstract

Purpose: Organic anion-transporting polypeptides (OATP) mediate the cellular uptake of a broad range of drugs. The hydrophobic anticancer drug, paclitaxel (PTX), was recently identified as a substrate for OATP1B3 in vitro. We investigated the role of Oatp1a/1b transporters in the pharmacokinetics of PTX in vivo, as well as their impact at different dose levels of PTX and methotrexate (MTX).Experimental Design: Recently generated Slco1a/1b À/À (lacking all Oatp1a/1b transporters) and wildtype mice were intravenously dosed with 2, 10, or 50 mg/kg of PTX, or with 10, 50, or 500 mg/kg of MTX, and plasma and tissue drug concentrations were measured.Results: In spite of its hydrophobicity, PTX systemic exposure (at 10 mg/kg) was increased by greater than 2-fold in Slco1a/1b À/À mice compared with wild-type, whereas PTX liver uptake was reduced by about 2-fold. Oatp1a/1b transporters displayed a high impact on PTX and MTX pharmacokinetics over a broad dose range. For MTX, even at 500 mg/kg, saturation of Oatp1a/1b was not observed, with a 3.4-fold increase in plasma and 30-fold decrease in liver levels in Slco1a/1b À/À mice compared with wild-type.Although beginning saturation of Oatp1a/1b was observed at the highest dose of PTX, plasma levels in Slco1a/1b À/À mice were still 1.7-fold increased and liver levels 1.5-fold decreased compared with wild-type.Conclusion: Oatp1a/1b transporters play a pronounced role in determining plasma levels and tissue distribution of MTX and PTX, thus affecting even highly hydrophobic drugs. Variation in OATP1A/1B transporter activity, due to genetic variation, inhibition, and/or tumor expression might affect toxicity and therapeutic efficacy of these anticancer drugs.

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

“…In particular, we previously reported that paclitaxel and docetaxel are transported substrates of human OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) (14)(15)(16)(17), as well as the single functional homolog OATP1B2 (Slco1b2) in mice (18) and rats (18,29). These findings have been independently verified (30)(31)(32)(33)(34), and are consistent with in vitro studies that have identified paclitaxel as a potent inhibitor of OATP1B1-(35, 36) and OATP1B3-mediated transport (35,37,38). However, none of the other known 9 human OATPs or other rodent OATPs are capable of transporting paclitaxel (39), and similar results have been obtained with docetaxel (40).…”

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

“…Given the large overlap in tissue distribution and substrate specificity within the OATP1 family, another transgenic mouse model deficient for all five established Slco1a and Slco1b genes (Slco1a/1b −/− mice) has also been developed (54). These mice lacking Oatp1a1, Oatp1a4, Oatp1a5, Oatp1a6, and Oatp1b2 displayed drastically reduced hepatic uptake of methotrexate, fexofenadine, and paclitaxel and subsequently increased systemic exposure for all of these drugs (54,55).…”

Influence of Human OATP1B1, OATP1B3, and OATP1A2 on the Pharmacokinetics of Methotrexate and Paclitaxel in Humanized Transgenic Mice

“…Briefly, in the absence of Oatp1a/1b transporters, plasma levels of methotrexate and paclitaxel were markedly increased, whereas hepatic uptake and biliary excretion were significantly decreased (15,16). Methotrexate and paclitaxel are structurally diverse anticancer drugs, with methotrexate being a charged organic anion and paclitaxel a highly hydrophobic drug.…”

“…To overcome these limitations, we have now generated humanized OATP1B1, OATP1B3, and OATP1A2 transgenic mice (Slco1a/1b À/À ;1B1 tg , Slco1a/1b À/À ;1B3 tg , and Slco1a/ 1b À/À ;1A2 tg , respectively) with liver-specific expression of each of the transgenic cDNAs in an Oatp1a/1b knockout background. Transgenic expression in liver parenchyme cells (hepatocytes) was chosen in view of the exclusive liver expression and basolateral (sinusoidal) hepatocyte localization of OATP1B1 and OATP1B3 in humans, and the previously established prominent pharmacokinetic role of mouse Oatp1a/1b transporters in the liver (15,16). Preliminary partial physiologic analysis of 2 of these 3 mouse models has shown the importance of human OATP1B1 and OATP1B3 in bilirubin detoxification by the liver.…”