Losartan Competitively Inhibits CYP2C8-Dependent Paclitaxel Metabolism in Vitro

• Published in: Biological & pharmaceutical bulletin Vol. 37; no. 9; pp. 1550 - 1554
• Main Authors: Toda, Takaki, Rane, Anders, Inotsume, Nobuo, Eliasson, Erik, Mukai, Yuji, Hayakawa, Toru
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 2014; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Angiotensin II Type 1 Receptor Blockers - pharmacology; Antihypertensive Agents - pharmacology; Antineoplastic Agents, Phytogenic - pharmacology; Cells, Cultured; CYP2C8; Cytochrome P-450 CYP2C8 - metabolism; Cytochrome P-450 CYP2C8 Inhibitors - pharmacology; Drug Interactions; drug–drug interaction; Humans; losartan; Losartan - pharmacology; Microsomes - metabolism; paclitaxel; Paclitaxel - pharmacology
• ISSN: 0918-6158; 1347-5215; 1347-5215
• DOI: 10.1248/bpb.b14-00366

The present study aimed to characterize the inhibitory effects of losartan, an angiotensin II receptor blocker, on CYP2C8. Inhibition experiments were based on human lymphoblast-expressed recombinant CYP2C8 (rCYP2C8) and paclitaxel as a CYP2C8 substrate. The disappearance of paclitaxel (initial concentration: 7.5 µmol/L) was monitored over time at different concentrations of losartan (0, 100, 500 and 1000 µmol/L). For Dixon and Cornish–Bowden plots, various concentrations of losartan (final concentration: 0, 50, 100 and 250 µmol/L) and paclitaxel (final concentration: 3.75, 7.5 and 15 µmol/L) were used. Losartan exhibited significant inhibitory effects on paclitaxel disappearance at losartan concentrations of ≥100 µmol/L (p<0.05). Losartan at 50 µmol/L inhibited the disappearance of paclitaxel by about 60%. Both plots showed that losartan exerted competitive inhibition of rCYP2C8, and its apparent Ki value was estimated to be 40.7 µmol/L. The degree of inhibition (R value) for rCYP2C8 after oral administration of losartan (100 mg) was estimated to be 1.2, using the maximum hepatic input total blood concentration (7.3 µmol/L). The present results show that losartan acts as a competitive inhibitor of CYP2C8-dependent drug metabolism in vitro. Subjects with a low clearance of losartan, resulting in a high average systemic blood concentration of losartan after repeated oral administration, should be carefully monitored for possible adverse reactions during co-medication with CYP2C8 substrate drugs.