Functional impact of CYP2C*5, CYP2C9*6, CYP2C9*8, and CYP2C9*11 in vivo among black Africans

被引:72
作者
Allabi, AC
Gala, JL
Horsmans, Y
Babaoglu, MO
Bozkurt, A
Heusterspreute, M
Yasar, U
机构
[1] Catholic Univ Louvain, St Luc Univ Hosp, Ctr Human Genet, B-1200 Brussels, Belgium
[2] Catholic Univ Louvain, St Luc Univ Hosp, Clin Pharmacol Unit, B-1200 Brussels, Belgium
[3] Hacettepe Univ, Fac Med, Dept Pharmacol, TR-06100 Ankara, Turkey
关键词
D O I
10.1016/j.clpt.2004.04.001
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background and Aim: Previous data indicate that the urinary losartan/E-3174 ratio is a marker for cytochrome P450 (CYP) 2C9 activity in vivo. The functional impact of CYP2C9(star)5, (star)6, (star)8, and (star)11 polymorphisms in vivo has not been investigated previously in humans. Methods: A single oral dose of losartan (25 mg) was given to 19 Beninese subjects with CYP2C9(star)1/(star)1 (n = 9), (star)1/(star)5 (n = 1), (star)1/(star)6 (n = 1), (star)1/(star)8 (n = 2), (star)1/(star)11 (n = 3), (star)5/(star)6 (n = 1), (star)5/(star)8 (n = 1), and (star)8/(star)11 (n = 1) genotypes. Concentrations of losartan and its active metabolite E-3174 were determined in urine from 0 to 8 hours by HPLC. The losartan/E-3174 metabolic ratio was used as a measure of losartan oxidation in vivo. Results: The urinary losartan/E-3174 ratio in the various genotypes was as follows: 1.85 +/- 2.4 (mean +/- SD) for CYP2C9(star)1/(star)1, 14.6 for CYP2C9(star)1/star5, 4.2 for CYP2C9(star)1/(star)6, 188 for CYP2C9(star)5/(star)6, 11.6 for CYP2C9(star)5/(star)8, 0.44 +/- 0.13 (mean +/- SD) for CYP2C9(star)1/(star)8, 2.2 for CYP2C9(star)8/(star)11, and 5.72 +/- 4.5 (mean +/- SD) for CYP2C9(star)1/(star)11. Compared with the CYP2C9(star)1/(star)1 genotypes, the losartan/E-3174 ratio was significantly different in the CYP2C9(star)5 allele carriers (CYP2C9(star)1/(star)5, CYP2C9(star)5/(star)8, and CYP2C9(star)5/(star)6 genotypes) (P = .01, Mann-Whitney) but was not different in CYP2C9(star)1/(star)8 (P = .16) and CYP2C9(star)1/(star)11 (P = .11) carriers. The urinary losartan/E-3174 ratio of the single CYP2C9(star)1/(star)6 subject was higher than the 95% confidence interval of the mean of the CYP2C9(star)1/(star)1 group (0.0-3.7), whereas the metabolic ratio of the CYP2C9(star)8/(star)11 carrier was inside the 95% confidence interval of the means of the CYP2C9(star)1/(star)1 and CYP2C9(star)1/(star)11 groups (0.0-18). Conclusions: The CYP2C9(star)5 and (star)6 alleles are associated with decreased enzyme activity in vivo compared with the wild-type variant, whereas the CYP2C9(star)8 and (star)11 variants did not appear to have large in vivo effects.
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页码:113 / 118
页数:6
相关论文
共 30 条
  • [21] Genetic polymorphism of cytochrome P4502C9 in a Caucasian and a black African population
    Scordo, MG
    Aklillu, E
    Yasar, U
    Dahl, ML
    Spina, E
    Ingelman-Sundberg, M
    [J]. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2001, 52 (04) : 447 - 450
  • [22] Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects
    Sekino, K
    Kubota, T
    Okada, Y
    Yamada, Y
    Yamamoto, K
    Horiuchi, R
    Kimura, K
    Iga, T
    [J]. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 2003, 59 (8-9) : 589 - 592
  • [23] Genetic polymorphisms and functional characterization of the 5′-flanking region of the human CYP2C9 gene:: In vitro and in vivo studies
    Shintani, M
    Ieiri, I
    Inoue, K
    Mamiya, K
    Ninomiya, H
    Tashiro, N
    Higuchi, S
    Otsubo, K
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 2001, 70 (02) : 175 - 182
  • [24] Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients
    Takahashi, H
    Wilkinson, GR
    Caraco, Y
    Muszkat, M
    Kim, RB
    Kashima, T
    Kimura, S
    Echizen, H
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 2003, 73 (03) : 253 - 263
  • [25] Altered pharmacokinetics and excessive hypotensive effect of candesartan in a patient with the CYP2C9*1/*3 genotype
    Uchida, S
    Watanabe, H
    Nishio, S
    Hashimoto, H
    Yamazaki, K
    Hayashi, H
    Ohashi, K
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 2003, 74 (05) : 505 - 508
  • [26] VALIDATION OF THE TOLBUTAMIDE METABOLIC RATIO FOR POPULATION SCREENING WITH USE OF SULFAPHENAZOLE TO PRODUCE MODEL PHENOTYPIC POOR METABOLIZERS
    VERONESE, ME
    MINERS, JO
    RANDLES, D
    GREGOV, D
    BIRKETT, DJ
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 1990, 47 (03) : 403 - 411
  • [27] Analysis of CYP2C9*5 in Caucasian, Oriental and black-African populations
    Yasar, Ü
    Aklillu, E
    Canaparo, R
    Sandberg, M
    Sayi, J
    Roh, HK
    Wennerholm, A
    [J]. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 2002, 58 (08) : 555 - 558
  • [28] Intra-individual variability in urinary losartan oxidation ratio, an in vivo marker of CYP2C9 activity
    Yasar, Ü
    Dahl, ML
    Christensen, M
    Eliasson, E
    [J]. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2002, 54 (02) : 183 - 185
  • [29] Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CΥP2C9 genotype
    Yasar, Ü
    Forslund-Bergengren, C
    Tybring, G
    Dorado, P
    Llerena, A
    Sjöqvist, F
    Eliasson, E
    Dahl, ML
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 2002, 71 (01) : 89 - 98
  • [30] Yasar Ü, 2001, DRUG METAB DISPOS, V29, P1051