title: 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 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.
authors.affiliation: Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mukai
authors.forename: Takaki
authors.initials: T
authors.lastname: Toda
authors.forename: Toru
authors.initials: T
authors.lastname: Hayakawa
authors.forename: Erik
authors.initials: E
authors.lastname: Eliasson
authors.forename: Anders
authors.initials: A
authors.lastname: Rane
authors.forename: Nobuo
authors.initials: N
authors.lastname: Inotsume
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002478:Cells, Cultured; D065727:Cytochrome P-450 CYP2C8 / Q000378:metabolism*; D065687:Cytochrome P-450 CYP2C8 Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D019808:Losartan / Q000494:pharmacology*; D008861:Microsomes / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D000972:Antineoplastic Agents, Phytogenic; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D065727:Cytochrome P-450 CYP2C8; D019808:Losartan; D017239:Paclitaxel