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Chlorpropamide 2‐hydroxylation is catalysed by CYP2C9 and CYP2C19 in vitro : chlorpropamide disposition is influenced by CYP2C9, but not by CYP2C19 genetic polymorphism
Author(s) -
Shon JiHong,
Yoon YoungRan,
Kim MinJung,
Kim KyoungAh,
Lim YoungChae,
Liu KwangHyeon,
Shin DongHoon,
Lee Chung Han,
Cha InJune,
Shin JaeGook
Publication year - 2005
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2005.02364.x
Subject(s) - chlorpropamide , cyp2c19 , cyp2c9 , microsome , metabolite , endocrinology , chemistry , mephenytoin , medicine , pharmacology , cytochrome p450 , biochemistry , biology , metabolism , in vitro , diabetes mellitus
Aims We evaluated the involvement of cytochrome P450 (CYP) isoforms 2C9 and 2C19 in chlorpropamide 2‐hydroxylation in vitro and in chlorpropamide disposition in vivo . Methods To identify CYP isoforms(s) that catalyse 2‐hydroxylation of chlorpropamide, the incubation studies were conducted using human liver microsomes and recombinant CYP isoforms. To evaluate whether genetic polymorphisms of CYP2C9 and/or CYP2C19 influence the disposition of chlorpropamide, a single oral dose of 250 mg chlorpropamide was administered to 21 healthy subjects pregenotyped for CYP2C9 and CYP2C19. Results In human liver microsomal incubation studies, the formation of 2‐hydroxychlorpropamide (2‐OH‐chlorpropamide), a major chlorpropamide metabolite in human, has been best described by a one‐enzyme model with estimated K m and V max of 121.7 ± 19.9 µ m and 16.1 ± 5.0 pmol min −1 mg −1 protein, respectively. In incubation studies using human recombinant CYP isoforms, however, 2‐OH‐chlorpropamide was formed by both CYP2C9 and CYP2C19 with similar intrinsic clearances (CYP2C9 vs. CYP2C19: 0.26 vs. 0.22 µl min −1 nmol −1 protein). Formation of 2‐OH‐chlorpropamide in human liver microsomes was significantly inhibited by sulfaphenazole, but not by S ‐mephenytoin, ketoconazole, quinidine, or furafylline. In in vivo clinical trials, eight subjects with the CYP2C9 * 1/ * 3 genotype exhibited significantly lower nonrenal clearance [* 1/ * 3 vs. * 1/ * 1 : 1.8 ± 0.2 vs. 2.4 ± 0.1 ml h −1 kg −1 , P < 0.05; 95% confidence interval (CI) on the difference 0.2, 1.0] and higher metabolic ratios (of chlorpropamide/2‐OH‐chlorpropamide in urine: * 1/ * 3 vs. * 1/ * 1 : 1.01 ± 0.19 vs. 0.56 ± 0.08, P < 0.05; 95% CI on the difference − 0.9, − 0.1) than did 13 subjects with CYP2C9 * 1/ * 1 genotype. In contrast, no differences in chlorpropamide pharmacokinetics were observed for subjects with the CYP2C19 extensive metabolizer vs. poor metabolizer genotypes. Conclusions These results suggest that chlorpropamide disposition is principally determined by CYP2C9 activity in vivo , although both CYP2C9 and CYP2C19 have a catalysing activity of chlorpropamide 2‐hydroxylation pathway.