Losartan Competitively Inhibits CYP2C8-Dependent Paclitaxel Metabolism in Vitro

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 conc...

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Bibliographic Details
Published in:Biological & pharmaceutical bulletin 2014/09/01, Vol.37(9), pp.1550-1554
Main Authors: Mukai, Yuji, Toda, Takaki, Hayakawa, Toru, Eliasson, Erik, Rane, Anders, Inotsume, Nobuo
Format: Article
Language:English
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
Medicin och hälsovetenskap
Microsomes - metabolism
paclitaxel
Paclitaxel - pharmacology
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Summary: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
ISSN:0918-6158
1347-5215
1347-5215
DOI:10.1248/bpb.b14-00366