Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3.
Human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8) are responsible for renal tubular secretion of an antifolic acid methotrexate, and are considered to be involved in drug interaction of methotrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). In our hospital, a delay of methotrexate elimination was experienced in a patient with Hodgkin's disease, who took loxoprofen, a commonly used NSAID in Japan, which suggested a cause. In this study, we examined the drug interaction via hOAT1 and hOAT3, using Xenopus laevis oocytes. hOAT1 and hOAT3 mediated the methotrexate transport with low affinity (K(m) of 724.0 muM) and high affinity (K(m) of 17.2 muM), respectively. Loxoprofen and its trans-OH metabolite, an active major metabolite, markedly inhibited the methotrexate transport by both transporters. Their inhibition concentrations (IC(50)) were in the range of the therapeutic levels. These findings suggest that loxoprofen retards the elimination of methotrexate, at least in part, by inhibiting hOAT1 and hOAT3.
Uwai
Yuichi
Y
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Taniguchi
Risa
R
Motohashi
Hideyuki
H
Saito
Hideyuki
H
Okuda
Masahiro
M
Inui
Ken-ichi
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D018076:DNA, Complementary / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000096:biosynthesis / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis / Q000378:metabolism*; D010666:Phenylpropionates / Q000378:metabolism / Q000494:pharmacology*; D014982:Xenopus laevis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000964:Antimetabolites, Antineoplastic; D018076:DNA, Complementary; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D010666:Phenylpropionates; C114338:organic anion transport protein 3; C040656:loxoprofen; D008727:Methotrexate