Chang M, Dahl M L, Tybring G, Götharson E, Bertilsson L
Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Sweden.
Pharmacogenetics. 1995 Dec;5(6):358-63. doi: 10.1097/00008571-199512000-00004.
A single oral dose of omeprazole (20 mg) was given orally to 160 healthy Caucasian Swedish subjects and tested as a probe for CYP2C19. The study was nonrandomized and included seven subjects previously classified as poor metabolizers (PM) of S-mephenytoin. The ratio between the plasma concentrations of omeprazole and hydroxyomeprazole (metabolic ratio; MR) was determined by HPLC in a blood sample drawn 3 h after drug intake. In 17 subjects the test was repeated and the MRs of omeprazole on the two occasions were correlated (rs = 0.85; p < 0.0001). There was a significant correlation between the MR of omeprazole and the S/R mephenytoin ratio among 141 subjects, in whom both ratios were determined (rs = 0.63, p < 0.001). All seven PMs of S-mephenytoin had higher MRs of omeprazole (7.1-23.8) than extensive metabolizers (EM) (0.1-4.9). All 160 subjects and another 15 Caucasian Swedish PMs previously phenotyped with mephenytoin were analysed with respect to the presence of the CYP2C19m1 allele by PCR amplification of the intron 4/exon 5 junction followed by Sma I digestion. EMs heterozygous for the CYP2C19m1 gene had MRs of omeprazole and S/R ratios of mephenytoin that were higher than those of subjects who were homozygous for the wild-type allele (p = 0.0001). Nineteen of the 22 PMs were homozygous for the CYP2C19m1 gene. Three were heterozygous for this allele. Thus, 41 of the 44 alleles (93%) of PMs were defective CYP2C19m1. One of the remaining three PM alleles was subsequently found to contain the CYP2C19m2 mutation, which has earlier been shown to be associated with the PM phenotype in Oriental populations. In conclusion, the phenotype determined by omeprazole correlated with that of mephenytoin, and was in good agreement with the genotype.
对160名健康的瑞典白种人受试者口服单剂量奥美拉唑（20毫克），并将其作为CYP2C19的探针进行测试。该研究未进行随机分组，包括7名先前被归类为S-美芬妥英代谢缓慢者（PM）的受试者。在服药3小时后采集的血样中，通过高效液相色谱法测定奥美拉唑和羟基奥美拉唑的血浆浓度之比（代谢率；MR）。对17名受试者重复进行该测试，并对两次测试中奥美拉唑的MR进行相关性分析（rs = 0.85；p < 0.0001）。在141名同时测定了两种比值的受试者中，奥美拉唑的MR与S/R美芬妥英比值之间存在显著相关性（rs = 0.63，p < 0.001）。所有7名S-美芬妥英的PM的奥美拉唑MR（7.1 - 23.8）均高于代谢正常者（EM）（0.1 - 4.9）。通过对内含子4/外显子5连接处进行PCR扩增，随后进行Sma I酶切，分析了所有160名受试者以及另外15名先前用美芬妥英进行表型分析的瑞典白种人PM中CYP2C19m1等位基因的存在情况。CYP2C19m1基因杂合的EMs的奥美拉唑MR和美芬妥英的S/R比值高于野生型等位基因纯合的受试者（p = 0.0001）。22名PM中有19名是CYP2C19m1基因纯合子。3名是该等位基因杂合子。因此，44个PM等位基因中有41个（93%）是缺陷型CYP2C19m1。随后发现其余三个PM等位基因中的一个含有CYP2C19m2突变，该突变先前已被证明与东方人群的PM表型相关。总之，由奥美拉唑确定的表型与美芬妥英的表型相关，且与基因型高度一致。
