Abstract
Organic anion-transporting polypeptide (OATP) drug uptake transporters are thought to play an important role in drug pharmacokinetics and toxicokinetics. We aimed to determine the influence of the individual human OATP1B1, OATP1B3, and OATP1A2 transporters on the in vivo disposition of the anticancer drugs methotrexate and paclitaxel by using liver-specific humanized OATP1A/1B transgenic mice. Wild-type, Slco1a/1b(-/-) (Oatp1a/1b knockout), Slco1a/1b(-/-);1B1(tg), Slco1a/1b(-/-);1B3(tg), and newly generated Slco1a/1b(-/-);1A2(tg) (humanized OATP1B1, OATP1B3, and OATP1A2 transgenic) mice were characterized biochemically and physiologically, and subsequently intravenously dosed with methotrexate or paclitaxel (2 or 10 mg/kg each) for pharmacokinetic analyses. Humanized OATP1B1, OATP1B3, and OATP1A2 transgenic mice all showed partial or complete rescue of increased plasma bilirubin levels, but also of the increased plasma levels and decreased liver and small intestinal accumulation of methotrexate observed in Slco1a/1b(-/-) mice. Furthermore, hepatic expression of OATP1B3 and OATP1A2, but not OATP1B1, resulted in increased liver uptake of paclitaxel (2 mg/kg). At 10 mg/kg, a modest effect of only OATP1A2 on paclitaxel liver uptake was observed. Human OATP1A/1B transporters play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutics methotrexate (organic anion) and paclitaxel (hydrophobic, bulky). Variation in OATP1A/1B activity due to genetic variation and pharmacologic inhibition, or differences in tumor-specific expression levels might therefore affect plasma, tissue, and tumor levels of these drugs in patients, and hence their therapeutic efficacy. Humanized transgenic OATP1A/1B mice will provide excellent tools to further study these aspects in vivo for many (anticancer) drugs.
Highlights
Organic anion-transporting polypeptides (OATP; gene name: SLCO) are transmembrane transporters that can mediate the cellular uptake of a broad range of substrates
Using humanized OATP1B1, -1B3, and -1A2 transgenic mice, we found that all 3 human proteins transport the anticancer drug methotrexate in vivo, whereas only OATP1B3 and OATP1A2 transport paclitaxel
Low levels of OATP1A2 in a total human liver preparation reflect the fact that this protein is restricted to cholangiocytes, which only form a small fraction of the total liver cell pool [9]
Summary
Organic anion-transporting polypeptides (OATP; gene name: SLCO) are transmembrane transporters that can mediate the cellular uptake of a broad range of substrates. OATPs are classified into 6 distinct families and currently 11 human and 15 mouse OATPs/Oatps. Authors' Affiliations: 1Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; and 2Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, United Kingdom. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Current address for E. van de Steeg: Pharmacokinetics and Human Studies, TNO, Zeist, the Netherlands. Within the OATP1 family, based on amino acid homology, no clear and direct orthologs between individual human and mouse OATPs exist. While humans only have one OATP1A transporter (OATP1A2), mice have at least 4 While humans have 2 OATP1B transporters (OATP1B1 and OATP1B3), mice only have one, Oatp1b2 [2]
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