丙戊酸药物浓度与CYP2C19基因多态性关系的研究

目的：寻找丙戊酸药物浓度与CYP2C19基因多态性的关系，以便临床根据患者的基因型进行个体化给药。方法：运用血药浓度监测仪测定患者血药浓度和变性高效液相色谱法检测癫痫患者的CYP2C19基因多态性位点．对二者结果进行相关性分析。结果：51名汉族癫痫患者中有29名携带突变型CYP2C19基因，其中19名(65．52％)患者丙戊酸实际血药浓度较预期的血药浓度升高，血药浓度分布曲线右移。结论：CYP2C19参与丙戊酸的代谢。对于含突变型CYP2C19基因的患者应给予小剂量丙戊酸，以减少药物不良反应的发生和药物资源的浪费。     

中国汉族癫痫患者CYP2C19和CYP2C9基因多态性对苯妥英钠血药浓度的影响

目的 研究中国汉族癫痫患者细胞色素P450(CYP450)2C19和2C9基因多态性对苯妥英钠血药浓度的影响.方法 用PCR-RFLP方法,分析82例患者的CYP2C19*2,*3及CYP2C9*3这3个单碱基突变位点,用荧光偏振免疫法(FPIA)测定苯妥英钠血药浓度.结果 CYP2C9*3*、CYP2C19*2及CYP2C19*3等位基因频率分别为7.3%,33.5%和3.7%.强、中间、弱代谢组间的标准化血药浓度差别显著(P=0.000).苯妥英钠血药浓度的多元线性回归中,CYP2C19*2、CYP2C19*3、CYP2C9*3这3个基因突变位点beta值分别为5.71,6.65,6.95.结论 基因突变导致苯妥英钠血药浓度升高,且与突变位点的数量有关.     

CYP2C9与CYP2C19基因多态性与癫痫患者丙戊酸血药浓度关系研究

目的:探讨细胞色素氧化酶P450 2C9(CYP2C9)和CYP2C19基因型对癫痫患者丙戊酸血药浓度的影响.方法:对40例癫痫患者应用限制性酶切片段多态性技术分析中国人常见的1个CYP2C9和2个CYP2C19等位基因变异,应用荧光偏振免疫法测定患者丙戊酸的血药浓度,在进行标准化以排除剂量和体重对血药浓度的影响后,分析CYP2C9、CYP2C19基因型和丙戊酸血药浓度的关系.结果:根据携带CYP2C9和CYP2C19突变等位基因的数量,将患者分为基因型CYP2C911合并CYP2C1911的野生型纯合子强代谢者(EM).基因型为CYP2C913或CYP2C1912或CYP2C1913的杂合中等代谢者(IM),基因型为CYP2C933或CYP2C913合并CYP2C1913或CYP2C1922的突变型纯合子弱代谢者(PM).三组频率分别为47.5%、25%和27.5%.并且突变基因携带数量与标准化血药浓度呈正相关.PM患者服用等剂量丙戊酸时血药浓度比EM患者高(P<0.05).结论:丙戊酸代谢受CYP2C9和CYP2C19基因调控.检测患者CYP2C9和CYP2C19基因型可以预测患者药物浓度,有利于临床选择适宜的丙戊酸初始剂量.     

影响颅内恶性肿瘤患者体内苯妥英钠血药浓度的相关因素

目的:探讨苯妥英钠预防颅内恶性肿瘤患者手术后癫痫的血药浓度与其体内病理生理因素及合并用药的相关性,为临床合理使用苯妥英钠提供参考。方法:收集133例次颅内肿瘤患者手术后使用苯妥英钠预防癫痫的病历资料,记录患者性别、年龄、体质量、血药浓度、CYP2C9和CYP2C19基因多态性,以及相应生化检验值。应用SAS软件(6.04&8.0版)对数据进行多元线性回归分析。结果:苯妥英钠血药浓度与年龄和体质量之间存在明显正相关性(P<0.05),但与CYP2C9基因多态性呈明显负相关性(P<0.05)。结论:应主要从患者年龄、体质量以及CYP2C9基因多态性的角度,设计苯妥英钠的个体化剂量方案。     

CYP2D6 CYP2C19*2基因多态性与利培酮治疗精神分裂症临床效应的相关研究

目的探讨CYP2D6和CYP2C19基因多态性与利培酮治疗精神分裂症临床效应个体差异之间的相关性。方法应用聚合酶链反应(PCR)与DNA测序相结合的方法检测精神分裂症患者CYP2D6和CYP2C19基因多态性。应用高效液相色谱分别测定利培酮、9-羟利培酮的血药浓度,以治疗前后阳性和阴性症状量表(PANSS)评分减分率评价药物临床疗效,比较不同基因型之间血药浓度和药物临床疗效的差异。结果55例单用利培酮治疗的精神分裂症患者,CYP2D6(C100T)不同基因型之间利培酮血药浓度分布差异有统计学意义(P<0.05),但该位点与该药的临床效应之间没有相关性(P>0.05)。CYP2C19*2(G681A)基因多态性与利培酮在体内代谢以及该药临床效应之间差异无统计学意义(P>0.05)。结论CYP2D6(C100T)对利培酮血药浓度有影响,但与利培酮的临床效应个体差异间无相关性。CYP2C19*2(G681A)可能不是引起利培酮代谢以及临床效应个体差异的主要因素。     

服用卡马西平癫痫患者CYP3A4基因多态性的研究

目的:研究服用卡马西平癫痫患者细胞色素P4503A4(CYP3A4)的基因多态性,为临床制定卡马西平个体化给药方案提供依据。方法:收集临床服用卡马西平癫痫患者的血标本,用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)法检测CYP3A4的突变。结果:141例患者中存在CYP3A4*4、CYP3A4*6的突变,个体突变率均为0.71%;未见CYP3A4*5的突变。结论:2例突变型标本与其他标本的血药浓度与临床疗效比较无显著性差异,不能说明CYP3A4*4、CYP3A4*6的突变对其表达的药物代谢酶的活性有影响。     

中国人群难治性癫痫患者CYP2C19*2基因型对癫痫耐药的影响

目的:研究中国人群难治性癫痫患者CYP2C19*2基因型对癫痫耐药的影响,促进阐明难治性癫痫的耐药机制。方法:采用聚合酶链反应(PCR)-限制性片段长度多态性(RFLP)方法对难治性癫痫患者(接受癫痫治痫灶切除的患者)和非难治性癫痫患者(单药有效的癫痫患者)的CYP2C19*2(681G→A)位点进行基因型分析,对患者杂合型和纯突变型的样本进行抽样测序验证,以确保基因分型结果准确。对两组基因和基因型频率采用卡方检验的统计学分析,选用SPSS12.0版软件进行处理。结果:收集了96例难治性癫痫患者和305例非难治性癫痫患者。CYP2C19*2等位基因频率:难治组G64.6%,A35.4%;非难治组:G67.9%,A32.1%;难治组突变基因频率高于非难治组但没有统计学差异(P>0.05)。CYP2C19*2基因型频率:难治组GG33.3%,GA62.5%,AA4.2%;非难治组GG44.6%,GA46.6%,AA8.9%。难治组和非难治组基因型频率具有统计学差异(P<0.05),难治组中GG型频率显著低于非难治组,GA型频率高于非难治组(P<0.05);而AA型频率在两组内虽然不同却没有统计学差异。另外,进行基因型组合后,只有无突变(GG)与突变(GA和AA)基因型频率在两组间有统计学差异(P<0.05),难治组突变基因型频率高于非难治性组(66.7%:55.4%)。结论:中国人群难治性癫痫患者与非难治性癫痫患者的CYP2C19*2基因型分布频率有统计学差异,难治性癫痫组CYP2C19*2突变基因型频率高于非难治组;癫痫耐药与CYP2C19*2基因型之间没有关联性,阐明癫痫耐药机制应更加关注多基因之间的联合作用尤其是影响脑组织局部药物浓度的基因。     

中国汉族人群S-美芬妥英4''-羟化酶的表型与基因分析

目的:研究中国汉族人群S-美芬妥英4'-羟化代谢遗传多态性.方法:以美芬妥英为探针药物采用手性毛细管气相色谱法测定尿中S-/R-MP浓度比值, 对90名志愿者进行了表型分型测定,应用PCR技术对其中的26名志愿者进行了S-美芬妥英4'-羟化酶(CYP2C19)基因分析.结果:表型分析结果,11人属慢代谢者(PM),S/R比值0.95;基因分析结果,6人为野生型纯合子(wt/wt);10人为杂合子(wt/m1和wt/m2),9人为CYP2C19m1突变型纯合子(m1/m1),1人为两突变型杂合子(m1/m2).结论:表型分析与基因分析结果显示了很好的相关性,本实验测得慢代谢者的频发率为12.2%,与文献报道相符.     

中国人CYPC19和CYP2C9等位基因多态性分析

目的 探讨细胞色素P450(CYP)2C19(CYP2C19)和CYP2C9在中国人群中的等位基因多态性分布,分析影响上述基因多态性的因素。方法 应用聚合酶链反应-变性高效液相(PCR-DHPLC)技术分析了150例癫痫患者CYP2C19外显子4(·3)、外显子5(·2)和CYP2C9外显子7(·3)的等位基因变异,现察这二种基因多态性在癫痫患者中分布的特征。结果 150例 癫痫患者CYP2C19·3、CYP2C19·2和CYP2C9·3均为野生型的发生率为38.7％,CYP2C19·2、CYP2C19·3和CYP2C9·3等位基因频率分别为34.3％、5.3％和7.3％.CYP2C19·2和CYP2C19·3等位基因分布频率存在性别之间的显著差异,p值分别为p<0.05、p<0.01;而CYP2C9·3的等位基因分布频率不存在性别之间的显著差异。CYP2C19基因型存在性别之阍的差异显著,p<0.01。存在CYP2C9·3等住基因多态性的个体一定出现CYP2C19·2的等住基因多态性。结论 性别因素可能对CYP2C19酶的活性产生影响,应用同时经CYP2C9和CYP2C19代谢的药物时,需进行基因型测定。     

老年共病患者使用伏立康唑时药物基因型与血药浓度的相关性分析

目的 分析老年共病患者在使用伏立康唑(VRC)时细胞色素P450(CYP450)基因型与血药浓度的相关性。方法 分析32例老年患者接受VRC治疗侵袭性真菌感染的遗传因素(CYP450基因多态性)和非遗传因素(患者的机体情况、基础疾病与合并用药)对VRC血药浓度的影响。结果 CYP2C19快代谢型和中等代谢型患者的VRC血药浓度中位数分别为4.64和3.93 mg·L^-1,CYP3A4 GG和GA型患者的VRC血药浓度中位数分别为3.17和5.00 mg·L^-1,CYP2C9 AA和AC/CC型患者的VRC血药浓度中位数分别为4.04和3.27 mg·L^-1,差异均有统计学意义(均P<0.05)。在非遗传因素中,患者的年龄、服用钙通道阻滞药和利尿药均是影响VRC血药浓度的独立因素(均P<0.05)。结论 CYP2C19、CYP3A4与CYP2C9基因多态性均会影响VRC血药浓度。在使用VRC之前建议行药物基因检测,在用药时不仅要关注药物间的相互作用,还要监测VRC血药浓度。     

Effect of a genetic polymorphism of CYP1A2 inducibility on the steady state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia

The effect of a genetic polymorphism of inducibility of cytochrome P450 (CYP) 1A2 on the steady state plasma concentrations (Css) of haloperidol and reduced haloperidol was studied to clarify if these Css are dependent on the CYP1A2 activity. The subjects were 101 Japanese schizophrenic inpatients receiving oral haloperidol 12 mg/d. The Css of haloperidol and reduced haloperidol were measured in duplicate by high performance liquid chromatographic method, and were corrected to the mean body weight. A point mutation from guanine (wild-type) to adenine (mutated-type) at position -2964 in the 5'-flanking region of CYP1A2 gene was identified by polymerase chain reaction (PCR)-fragment length polymorphism method. Based on the present results, i.e., significant effects of CYP2D6 genotypes on the Css of haloperidol and reduced haloperidol, analyses were separately performed in two groups, i.e., patients with 0 mutated allele of the CYP2D6 (41 cases) and those with 1 or 2 mutated alleles (60 cases). Subjects in each CYP2D6 genotype group consisted of 4 subgroups according to smoking habit and the presence of the mutated allele of the CYP1A2. Neither the Css of haloperidol nor that of reduced haloperidol significantly differed among the 4 subgroups in either CYP2D6 genotype group. The present study thus suggests that the CYP1A2 activity does not play an important role in controlling the Css of haloperidol or reduced haloperidol.     

The impact of CYP2C19 and CYP2D6 genotypes on metabolism of amitriptyline in Japanese psychiatric patients

We investigated the effect of the CYP2C19 and CYP2D6 genotypes on the metabolism of amitriptyline (AT) in Japanese psychiatric patients. Steady-state concentrations of AT and its metabolites (nortriptyline [NT], trans-10-hydroxy-nortriptyline [EHNT], cis-10-hydroxy-nortriptyline [ZHNT], trans-10-hydroxy-amitriptyline [EHAT], and cis-10-hydroxy-amitriptyline [ZHAT]) in 50 patients were determined by high-performance liquid chromatography. Significantly higher plasma concentrations of AT corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 were observed (no mutated alleles vs. two mutated alleles: 36.0 +/- 18.2 vs. 64.0 +/- 25.2 ng/mL/mg/kg, p = 0.025). A significantly higher AT/NT ratio was seen in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 (no mutated alleles vs. two mutated alleles: 1.27 +/- 0.59 vs. 3.40 +/- 1.02, p = 0.001). A trend for higher NT/EHNT ratio in the subjects with two mutated alleles of CYP2D6 than in those with no mutated alleles of CYP2D6 was observed (no mutated alleles vs. two mutated alleles: 0.73 +/- 0.39 vs. 1.31 +/- 0.81, p = 0.068). A trend for higher plasma concentrations of total hydroxylated metabolites of AT (EHAT + ZHAT) corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 was found (no mutated alleles vs. two mutated alleles: 9.5 +/- 5.8 vs. 17.8 +/- 8.9, p = 0.051). Therefore, the genotype of CYP2C19 is one of the important determinants of the plasma concentrations of AT and the capacity to desmethylate AT. Mother compound AT is shunted via hydroxylation pathways from AT to EHAT and ZHAT in the subjects with homozygotes of mutated alleles of CYP2C19 in order to compensate for the decreased capacity to desmethylate AT.     

Evaluation of phenytoin dosage regimens based on genotyping of CYP2C subfamily in routinely treated Japanese patients

Two research groups have reported the effect of genetic polymorphisms of CYP2C9 and CYP2C19 on the pharmacokinetic parameters of phenytoin in Japanese epileptic patients. We measured the plasma phenytoin concentrations at steady-state in 20 routinely treated Japanese patients, and evaluated the usefulness of genotyping the CYP2C subfamily in predicting plasma concentrations and determining the dosage regimens of phenytoin. The plasma phenytoin concentrations predicted by genotypes of the CYP2C subfamily were well correlated with the observed concentrations in some patients, but not in some patients. The pharmacokinetic parameters (Vmax and Km) in individual patients, which were obtained from population estimates according to Bayes' theorem, showed considerable interindividual variability even among patients with the same genotype. In addition, we assessed the effect of plasma protein binding on the residual interindividual variability in the clearance of phenytoin; however, there was no significant correlation between the unbound fraction and the intrinsic metabolic activity (Vmax/Km). These findings suggested that the mechanism responsible for the large variability in the clearance of phenytoin is not completely resolved, and that we should not overestimate the usefulness of genotyping the CYP2C subfamily in determining the dosage regimens of the drug.     

Influence of CYP2C9 genetic polymorphism and undernourishment on plasma-free phenytoin concentrations in epileptic patients

The objective of this study was to study the effect of CYP2C9 genetic polymorphism and undernourishment on free phenytoin concentrations in epileptic patients. The study was done in 70 patients who were taking phenytoin therapy for the treatment of epileptic seizures. Genotyping of CYP2C9 (*2 and *3) was determined by the polymerase chain reaction-restriction fragment length polymorphism method. Bound and free plasma phenytoin was separated using equilibrium dialysis technique. Total and free phenytoin concentrations were measured by the reverse-phase high-performance liquid chromatography method. Patients were broadly classified into well-nourished and undernourished and further subclassified by CYP2C9 genotypes. In well-nourished groups (G1 to G3 group), free phenytoin concentrations were significantly higher in the heterozygous poor metabolizer of CYP2C9 genotype (G2) group (3.1 ± 0.62 μg/mL) and homozygous poor metabolizer of CYP2C9 genotype (G3) group (4.3 ± 1.76 μg/mL) when compared with patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 μg/mL). Similarly, in undernourished patient groups (G4-G6 group), free phenytoin concentrations were significantly higher in the wild-type CYP2C9 (G4) group (2.5 ± 0.52 μg/mL), heterozygous poor metabolizer of CYP2C9 genotype (G5) group (4.3 ± 1.76 μg/mL), and homozygous poor metabolizer of CYP2C9 genotype (G6) group (8.2 ± 1.08 μg/mL) when compared with well-nourished patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 μg/mL). The percentage increase in free phenytoin concentration by undernourishment, CYP2C9 allelic variants, and undernourishment cum CYP2C9 allelic variants were 127%, 290%, and 472%, respectively, compared with well-nourished patients with the wild-type CYP2C9 genotype (G1) group. The contribution of undernourishment and genetic factors (CYP2C9 allelic variant) for developing phenytoin toxicity was calculated to have an odds ratio of 37.3 (P < 0.0001). Undernourishment and variant CYP2C9 alleles elevate free phenytoin concentrations individually and in combination show additive effects.     

Relationship between the CYP2D6 genotype and the steady-state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine

The relationship between the cytochrome P450 (CYP) 2D6 genotype and the steady-state plasma concentrations (Css) of trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) was studied in 54 depressed Japanese patients receiving trazodone 150 mg at bedtime. By use of allele-specific PCR analysis, the wild type allele, three mutated alleles causing absent enzyme activity (CYP2D6A, CYP2D6B and CYP2D6D) and one mutated allele causing decreased enzyme activity (CYPZD6 Ch) were identified. The means (ranges) of the Css of trazodone, corrected to the median body weight in 17 cases with no mutated allele, 27 cases with one mutated allele and 10 cases with two mutated alleles, were 556 (281–1115), 643 (302–1362) and 671 (234–1418) ng/ml, respectively, while the values of mCPP were 60 (35–121), 65 (33–99) and 58 (38–112) ng/ml, respectively. Neither the Css of trazodone (F = 0.80, P = 0.45) nor that of mCPP (F = 0.49, P = 0.61) significantly differed among the three groups. The present study thus suggests that the CYP2D6 genotype cannot predict the Css of these compounds. Received: 24 January 1997/Final version: 26 March 1997     

Association of galactose single-point test levels and phenytoin metabolic polymorphisms with gingival hyperplasia in patients receiving long-term phenytoin therapy

STUDY OBJECTIVE: To evaluate whether the occurrence or severity of gingival hyperplasia is associated with liver function test results or phenytoin metabolism. DESIGN: Prospective analysis. SETTING: University-affiliated medical center in Taipei, Taiwan. PATIENTS: Sixty-six patients (mean age 37.9 yrs) with epilepsy who were receiving phenytoin for more than 1 year. Intervention. Four blood samples were drawn from each patient for liver function testing, concentrations of phenytoin and its metabolites R-5-(4'-hydroxyphenyl)-5-phenylhydantoin (R-HPPH) and S-HPPH, and genotyping of cytochrome P450 (CYP) 2C9 and 2C19. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of phenytoin and its metabolites were determined by a high-performance liquid chromatography method. The CYP2C9 and CYP2C19 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism analysis. Conventional liver function assays and a quantitative liver function test--galactose single-point (GSP) measurement--were performed. Statistical analyses were performed to evaluate the association between liver function test results as well as metabolic phenotype and the occurrence and severity of gingival hyperplasia. Among liver function tests, only GSP levels showed a significant difference between patients with and those without gingival hyperplasia. Patients with an elevated GSP level (> or = 280 microg/ml) had a significantly higher odds ratio (OR 4.51) for the occurrence of gingival hyperplasia. In addition, increased R-HPPH (OR 1.02) and phenytoin (OR 1.09) concentrations were associated with an increased occurrence of gingival hyperplasia. However, only increased GSP and R-HPPH concentrations had significantly higher ORs (2.84 and 1.02, respectively) associated with the severity of gingival hyperplasia. Although mean +/- SD plasma R-HPPH concentration was significantly lower in CYP2C19 poor metabolizers compared with CYP2C9 and CYP2C19 extensive metabolizers and CYP2C9 poor metabolizers (30.38 +/- 16.73 vs 68.22 +/- 44.75 and 78.95 +/- 51.67 microg/ml, respectively), no significant association between genotype and gingival hyperplasia was found. CONCLUSION: Increased GSP, phenytoin, and R-HPPH concentrations were associated with increased occurrence of phenytoin-induced gingival hyperplasia; only increased GSP and R-HPPH concentrations were associated with increased severity of this adverse effect.     

Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients: interaction with CYP2C19 mutated alleles

OBJECTIVES: Administration of fluvoxamine (FLV) with concomitant benzodiazepines is common in clinical situations. We studied the effects of the coadministration of FLV on plasma concentrations of alprazolam (ALP). We also studied the effects of CYP2C19(*)2 or CYP2C19(*)3 on these drug interactions. METHODS: The subjects were 23 Japanese outpatients all concomitantly treated with FLV either before or after monotherapy with ALP. We measured the plasma concentrations of ALP and FLV using a column-switching, high-performance liquid chromatographic method with ultraviolet detection. The CYP2C19(*)2 or CYP2C19(*)3 alleles were identified using a polymerase chain reaction analysis. RESULTS: Coadministration with FLV produced significant, on average 58%, increases in the plasma concentrations of ALP ( P<0.001). There were, however, wide variations in the interactive effects of the coadministration of FLV on the plasma concentrations of ALP. While there were some subjects who had greater increases in plasma ALP concentrations, more than 100%, in response to the coadministration of FLV among the subjects with no mutated or one mutated allele, there are no subjects who had increases in plasma ALP concentrations of more than 50% among the subjects with two mutated alleles. The differences of these variances among the three genotype groups reached a level of significance ( P<0.05). CONCLUSION: Coadministration of FLV significantly increased the plasma concentrations of ALP compared with ALP monotherapy. Wide variations were observed in the drug interactions, with the CYP2C19 genotype possibly being related to these interactions.     

Effects of various CYP2D6 genotypes on the steady-state plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone,in Japanese patients with schizophrenia

The effects of various CYP2D6 genotypes on the steady-state plasma concentrations (Css) of risperidone and its active metabolite, 9-hydroxyrisperidone, were studied in 85 Japanese schizophrenic patients (27 men and 58 women) treated with 6 mg/d risperidone for at least 2 weeks. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-tandem mass spectrometry. The patients had the following CYP2D6 genotypes: wild-type (wt)/wt (40 patients), CYP2D6*10 (*10)/wt ( 28), CYP2D6*5 (*5)/wt ( 8), *10/*10 ( 5), *5/*10 ( 3), and CYP2D6*4/CYP2D6*14 ( 1), respectively. The Css values of risperidone and 9-hydroxyrisperidone were corrected to the median body weight of 58 kg. The medians (ranges) of the Css of risperidone in the aforementioned genotype groups were 2.2 (0.37-35.7), 6.4 (2.1-26.5), 12.3 (4.7-39.5), 19.4 (13.4-26.4), 64.0 (41.6-68.8), and 91.8 nmol/L. Those values for risperidone-to-9-hydroxyrisperidone ratio were 0.03 (0.01-0.33), 0.06 (0.03-0.19), 0.14 (0.07-0.29), 0.28 (0.25-0.38), 0.48 (0.38-0.58), and 2.35, respectively. The Css of risperidone was significantly (P < 0.05 or P < 0.001) different among the four genotype groups (wt/wt, *10/wt, *5/wt, and *10/*10), except between the *5/wt and *10/*10 groups. Also, the risperidone-to-9-hydroxyrisperidone ratio significantly (P < 0.005 or P < 0.001) differed among these genotype groups. No significant differences were found in the Css of 9-hydroxyrisperidone and the active moiety (the Css of risperidone plus 9-hydroxyrisperidone) among these genotype groups. This study confirms previous findings that the CYP2D6 status affects the Css of risperidone via its strong regulation of 9-hydroxylation of risperidone. However, similar active moiety of risperidone among different genotype groups suggests that the determination of the CYP2D6 genotype has little importance for clinical situations.     

CYP2C9, CYP2C19, ABCB1 (MDR1) genetic polymorphisms and phenytoin metabolism in a Black Beninese population

The genetically polymorphic cytochrome P450 2C9 (CYP2C9) metabolizes many important drugs. Among them, phenytoin has been used as a probe to determine CYP2C9 phenotype by measuring the urinary excretion of its major metabolite, S-enantiomer of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). Phenytoin pharmacokinetic is also dependent on the activity of CYP2C19 and p-glycoprotein (ABCB1). To determine the influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms on phenytoin metabolism in a Black population, 109 healthy Beninese subjects received a single 300 mg oral dose of phenytoin. Blood was drawn 4 h after drug intake and urine was collected during the first 8 h. Plasma phenytoin and urine S- and R-enantiomers of p-HPPH were determined by high-performance liquid chromatography. Urinary excretion of (S)-p-HPPH [defined as urinary volumex(S)-p-HPPH urinary concentration] and PMR (defined as the ratio of p-HPPH in urine to 4 h phenytoin plasma concentration), both markers of CYP2C9 activity, were used to determine the functional relevance of new variants of CYP2C9 (*5, *6, *8, *9 and *11) in this population. Plasma phenytoin concentration was significantly associated with ABCB1 haplotype/genotype (P=0.05, Kruskal-Wallis test) and levels increased significantly in the genotype order: wild-type, T3421A and Block-2 genotypes (P=0.015, Jonckheere-Terpstra test). Urinary excretion of (S)-p-HPPH and PMR were significantly associated with the CYP2C9 genotype (P=0.001, analysis of variance (ANOVA) and P<0.0001, Kruskal-Wallis test, respectively) and decreased in the order: CYP2C9*1/*1, CYP2C9*1/*9, CYP2C9*9/*9, CYP2C9*1/*8, CYP2C9*8/*9, CYP2C9*9/*11, CYP2C9*1/*5, CYP2C9*6/*9, CYP2C9*1/*6, CYP2C9*8/*11, CYP2C9*5/*8 and CYP2C9*5/*6 (P<0.001, Jonckheere-Terpstra test). A combined analysis of CYP2C9, 2C19 and ABCB1 revealed that only ABCB1 predicted phenytoin concentration at 4 h and explained 8% of the variability (r=0.08, P=0.04). On the other hand, only CYP2C9 was predictive for the urinary excretion of (S)-p-HPPH and PMR (r=0.21, P=0.001 and r=0.25, P<0.001, respectively). Furthermore, significant relation was found between urinary excretion of (R)-p-HPPH and CYP2C9 genotype (P=0.035) and levels significantly increased in the genotype order: CYP2C9*1/*9, CYP2C9*1/*1, CYP2C9*9/*11, CYP2C9*1/*8 and CYP2C9*1/*5 (P<0.001, Jonckheere-Terpstra test). In summary, the present study demonstrates that, in a Black population, CYP2C9*5, *6, *8 and *11 variants, but not CYP2C9*9, are associated with a decreased phenytoin metabolism. The data also confirm the limited contribution of MDR1 gene to inter-individual phenytoin pharmacokinetic variation.