Hou Z Y, Chen C P, Yang W C, Lai M D, Buchert E T, Chung H M, Pickle L W, Woosley R L
Department of Medicine, Veterans General Hospital, Kaohsiung, Republic of China.
Clin Pharmacol Ther. 1996 Apr;59(4):411-7. doi: 10.1016/S0009-9236(96)90109-5.
The polymorphic metabolism of debrisoquin and sparteine by cytochrome P450IID6 (CYP2D6) is genetically determined. Determination of the CYP2D6 metabolic phenotype with conventional urine analytic methods is not feasible in anuric patients with renal failure. The possibility of using salivary analysis, with dextromethorphan as a probe drug, to determine the CYP2D6 metabolic phenotype in patients with renal failure was evaluated.
One hundred four Chinese patients with renal failure were recruited. All 104 patients were receiving hemodialysis. Saliva was collected before and at 3 hours after each patient took a capsule of dextromethorphan hydrobromide (30 mg). Four patients were excluded because of insufficient samples of saliva. The distribution of logarithms of the metabolic ratios (log[MR]) in the 100 patients appeared to be normal. Administration of quinidine sulfate (200 mg twice daily) to nine of the patients significantly and markedly increased the dextromethorphan metabolic ratios. The metabolic ratios of nine patients pretreated with quinidine were higher than any of the 100 patients with renal failure who did not receive quinidine pretreatment. A metabolic ratio of 33 separated these two groups. Genomic deoxyribonucleic acid was extracted from whole blood in a subset of patients. Polymerase chain reaction (PCR)-based methods were used to detect the CYP2D6 and B mutant genes. Mutant B alleles (which are common in white poor metabolizers) of CYP2D6 genes were not detected in any of the 47 subjects tested. A PCR-based test of cytosine (C188) to thymine (T188) polymorphism at 188 base pairs in exon 1 of CYP2D6 genes was performed in 61 patients. Subjects who were homozygous for C188 had significantly (p = 0.0067) lower log[MR] values than those who were homozygous for T188.
Determination of dextromethorphan metabolic ratios in saliva is feasible in patients with renal failure requiring hemodialysis. All subjects in this study appeared to be "extensive metabolizer" phenotype for CYP2D6, and no poor metabolizer was identified. From the results with quinidine pretreatment, a metabolic ratio of 33 is suggested to be a tentative antimode for identification of poor metabolizers in patients with renal failure.
细胞色素P450IID6（CYP2D6）对异喹胍和司巴丁的多态性代谢由基因决定。对于肾衰竭的无尿患者，用传统尿液分析方法测定CYP2D6代谢表型是不可行的。本研究评估了以右美沙芬为探针药物，通过唾液分析来测定肾衰竭患者CYP2D6代谢表型的可能性。
招募了104例中国肾衰竭患者。所有104例患者均接受血液透析。在每位患者服用一粒氢溴酸右美沙芬胶囊（30mg）前及服药后3小时采集唾液。4例患者因唾液样本不足被排除。100例患者代谢比的对数（log[MR]）分布呈正态分布。9例患者每日两次服用硫酸奎尼丁（200mg）后，右美沙芬代谢比显著升高。9例接受奎尼丁预处理患者的代谢比高于100例未接受奎尼丁预处理的肾衰竭患者中的任何一例。代谢比为33可区分这两组患者。从部分患者的全血中提取基因组脱氧核糖核酸。采用基于聚合酶链反应（PCR）的方法检测CYP2D6和B突变基因。在47例受试对象中均未检测到CYP2D6基因的B突变等位基因（在白人慢代谢者中常见）。对61例患者进行了基于PCR的CYP2D6基因第1外显子188个碱基对处胞嘧啶（C188）到胸腺嘧啶（T188）多态性检测。C188纯合子受试者的log[MR]值显著低于T188纯合子受试者（p = 0.0067）。
对于需要血液透析的肾衰竭患者，测定唾液中右美沙芬代谢比是可行的。本研究中的所有受试者似乎均为CYP2D6的“广泛代谢者”表型，未发现慢代谢者。根据奎尼丁预处理的结果，建议代谢比为33作为识别肾衰竭患者慢代谢者的暂定反众数。
