Losartan competitively inhibits CYP2C8-dependent paclitaxel metabolism in vitro

Abstract

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 μ mol/L) was monitored over time at different concentrations of losartan (0, 100, 500 and 1000 μ mol/L). For Dixon and Cornish-Bowden plots, various concentrations of losartan (final concentration: 0, 50, 100 and 250 μ mol/L) and paclitaxel (final concentration: 3.75, 7.5 and 15 μ mol/L) were used. Losartan exhibited significant inhibitory effects on paclitaxel disappearance at losartan concentrations of ≥100 μ mol/L (p<0.05). Losartan at 50 μ mol/L inhibited the disappearance of paclitaxel by about 60%. Both plots showed that losartan exerted competitive inhibition of rCYP2C8, and its apparent Kivalue was estimated to be 40.7 μ mol/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 μ mol/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.