title: The Role of CYP2C8 and CYP2C9 Genotypes in Losartan-Dependent Inhibition of Paclitaxel Metabolism in Human Liver Microsomes.
abstract: The aim of the present study was to further investigate a previously identified metabolic interaction between losartan and paclitaxel, which is one of the marker substrates of CYP2C8, by using human liver microsomes (HLMs) from donors with different CYP2C8 and CYP2C9 genotypes. Although CYP2C8 and CYP2C9 exhibit genetic linkage, previous studies have yet to determine whether losartan or its active metabolite, EXP-3174 which is specifically generated by CYP2C9, is responsible for CYP2C8 inhibition. Concentrations of 6α-hydroxypaclitaxel and EXP-3174 were measured by high-performance liquid chromatography after incubations with paclitaxel, losartan or EXP-3174 in HLMs from seven donors with different CYP2C8 and CYP2C9 genotypes. The half maximal inhibitory concentration (IC50 ) values were not fully dependent on CYP2C8 genotypes. Although the degree of inhibition was small, losartan significantly inhibited the production of 6α-hydroxypaclitaxel at a concentration of 1 μmol/L in only HL20 with the CYP2C8*3/*3 genotype. HLMs with either CYP2C9*2/*2 or CYP2C9*1/*3 exhibited a lower losartan intrinsic clearance (Vmax /Km ) than other HLMs including those with CYP2C9*1/*1 and CYP2C9*1/*2. Significant inhibition of 6α-hydroxypaclitaxel formation by EXP-3174 could only be found at levels that were 50 times higher (100 μmol/L) than the maximum concentration generated in the inhibition study using losartan. These results suggest that the metabolic interaction between losartan and paclitaxel is dependent on losartan itself rather than its metabolite and that the CYP2C8 inhibition by losartan is not affected by the CYP2C9 genotype. Further study is needed to define the effect of CYP2C8 genotypes on losartan-paclitaxel interaction.
authors.affiliation: Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, Sapporo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mukai
authors.affiliation: Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, Sapporo, Japan.
authors.forename: Asuna
authors.initials: A
authors.lastname: Senda
authors.affiliation: Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, Sapporo, Japan.
authors.forename: Takaki
authors.initials: T
authors.lastname: Toda
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Eliasson
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Rane
authors.affiliation: Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, Sapporo, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Inotsume
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D020128:Inhibitory Concentration 50; D019808:Losartan / Q000378:metabolism / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects; D017239:Paclitaxel / Q000378:metabolism*; D043823:Taxoids / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; C086219:6-hydroxytaxol; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; C066026:losartan carboxylic acid; D019808:Losartan; D017239:Paclitaxel