TY - JOUR T1 - Alteration in the plasma concentrations of endogenous OATP1B-biomarkers in non-small cell lung cancer patients treated with paclitaxel JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.089474 SP - dmd.119.089474 AU - Daiki Mori AU - HIROO ISHIDA AU - Tadahaya Mizuno AU - Sojiro Kusumoto AU - Yusuke Kondo AU - Saki Izumi AU - Genki Nakata AU - Yoshitane Nozaki AU - Kazuya Maeda AU - Yasutsuna Sasaki AU - Ken-ichi Fujita AU - Hiroyuki Kusuhara Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/02/29/dmd.119.089474.abstract N2 - Paclitaxel has been considered to cause OATP1B-mediated drug–drug interactions at therapeutic doses; however, its clinical relevance has not been demonstrated. This study aimed to elucidate in vivo inhibition potency of paclitaxel against OATP1B1 and OATP1B3 using endogenous OATP1B biomarkers. Paclitaxel is an inhibitor of OATP1B1 and OATP1B3 with Ki of 0.579 ± 0.107 µM and 5.29 ± 3.87 µM, respectively. Preincubation potentiated its inhibitory effect on both OATP1B1 and OATP1B3 with Ki of 0.154 ± 0.031 µM and 0.624 ± 0.183 µM, respectively. Ten non-small cell lung cancer patients who received 200 mg/m2 of paclitaxel by a 3-h infusion were recruited. Plasma concentrations of 10 endogenous OATP1B biomarkers, namely, coproporphyrin I, coproporphyrin III, glycochenodeoxycholate-3-sulfate, glycochenodeoxycholate-3-glucuronide, glycodeoxycholate-3-sulfate, glycodeoxycholate-3-glucuronide, lithocholate-3-sulfate, glycolithocholate-3-sulfate, taurolithocholate-3-sulfate, and chenodeoxycholate-24-glucuronide, were determined in the non-small cell lung cancer patients on the day before paclitaxel administration, and after the end of paclitaxel infusion for 7 hours. Paclitaxel increased the area under the plasma concentration–time curve (AUC) of the endogenous biomarkers 2–4-fold although a few patients did not show any increment in the AUC ratios of lithocholate-3-sulfate, glycolithocholate-3-sulfate, and taurolithocholate-3-sulfate. Therapeutic doses of paclitaxel for the treatment of non-small cell lung cancer (200 mg/m2) will cause significant OATP1B1 inhibition during and at the end of the infusion. This is the first demonstration that endogenous OATP1B biomarkers could serve as surrogate biomarkers in patients.SIGNIFICANCE STATEMENT Endogenous biomarkers are able to address practical and ethical issues in elucidating transporter-mediated drug–drug risks of anticancer drugs clinically. In this study, we could elucidate a significant increment of the plasma concentrations of OATP1B endogenous biomarkers following a 3-h infusion (200 mg/m2) of paclitaxel, an inhibitor causing time-dependent inhibition of OATP1B1 and OATP1B3, in patients. The present study demonstrated that the endogenous OATP1B biomarkers are useful in patients to suggest the possibility of OATP1B-mediated DDI by paclitaxel, and help in designing dosing schedule to avoid drug–drug interactions. ER -