Losartan Competitively Inhibits CYP2C8-Dependent Paclitaxel Metabolism <i>in Vitro</i>

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  • Mukai Yuji
    Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy
  • Toda Takaki
    Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy
  • Hayakawa Toru
    Division of Pharmacotherapy, Hokkaido Pharmaceutical University School of Pharmacy
  • Eliasson Erik
    Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Karolinska Institute
  • Rane Anders
    Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Karolinska Institute
  • Inotsume Nobuo
    Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy

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  • Losartan Competitively Inhibits CYP2C8-Dependent Paclitaxel Metabolism in Vitro

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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 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.

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