Yasui-Furukori Norio, Mihara Kazuo, Takahata Takenori, Suzuki Akihito, Nakagami Taku, De Vries Ronald, Tateishi Tomonori, Kondo Tsuyoshi, Kaneko Sunao
Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki, Japan.
Br J Clin Pharmacol. 2004 May;57(5):569-75. doi: 10.1111/j.1365-2125.2003.02061.x.
An in vitro study has suggested that risperidone is a substrate of P-glycoprotein, which is coded by MDR-1 gene. Thus, we studied the effects of major polymorphisms of the MDR-1 gene on plasma drug concentrations.
Subjects were 85 schizophrenic patients receiving 3 mg twice daily of risperidone. Sample collections were conducted 12 h after the bedtime dosing. Plasma concentrations of risperidone and 9-hydroxyrisperidone were quantified using LC/MS/MS. MDR-1 genotypes (C3435T and G2677T/A) and CYP2D6 genotypes were identified using PCR-RFLP methods.
There was no difference in geometric mean (95% CI) of steady-state plasma concentration of risperidone between C3435T genotypes [C/C, C/T, T/T; 2.06 (1.63, 6.47), 2.96 (3.10, 7.91), 2.28 (1.81, 8.04) ng ml(-1), P = 0.759] or G2677T/A genotypes [G/G, G/T or A, T or A/T or A; 1.62 (0.08, 6.07), 2.64 (3.25, 7.10), 2.71 (2.77, 8.72) ng ml(-1), P = 0.625] or 9-hydroxyrisperidone between C3435T genotypes [38.3 (33.7, 50.1), 34.9 (32.9, 42.0), 35.7 (31.7, 42.3) ng ml(-1), P = 0.715] or G2677T/A genotypes [40.6 (33.0, 51.8), 35.0 (33.3, 42.4), 36.1 (32.8, 47.2) ng ml(-1), P = 0.601]. Multiple regression analyses including CYP2D6 genotypes, sex, and age revealed that steady-state plasma concentration of risperidone correlated with the number of mutated alleles for CYP2D6 (standardized partial correlation coefficients (beta) = 0.540, P < 0.001) and those of 9-hydroxyrisperidone (standardized beta = 0.244, P = 0.038) and active moiety (standardized beta = 0.257, P = 0.027) correlated with age.
These findings suggest that the MDR-1 variants are not associated with steady-state plasma concentration of risperidone or 9-hydroxyrisperidone, but CYP2D6 genotypes and age are determinants of these concentrations.
一项体外研究表明，利培酮是由多药耐药基因1（MDR-1）编码的P-糖蛋白的底物。因此，我们研究了MDR-1基因的主要多态性对血浆药物浓度的影响。
研究对象为85例接受每日两次3mg利培酮治疗的精神分裂症患者。在睡前给药12小时后进行样本采集。采用液相色谱-串联质谱法（LC/MS/MS）测定利培酮和9-羟基利培酮的血浆浓度。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法鉴定MDR-1基因型（C3435T和G2677T/A）和细胞色素P450 2D6（CYP2D6）基因型。
C3435T基因型[C/C、C/T、T/T；2.06（1.63，6.47）、2.96（3.10，7.91）、2.28（1.81，8.04）ng/ml，P = 0.759]或G2677T/A基因型[G/G、G/T或A、T或A/T或A；1.62（0.08，6.07）、2.64（3.25，7.10）、2.71（2.77，8.72）ng/ml，P = 0.625]的利培酮稳态血浆浓度几何均值（95%可信区间）无差异，C3435T基因型[38.3（33.7，50.1）、34.9（32.9，42.0）、35.7（31.7，42.3）ng/ml，P = 0.715]或G2677T/A基因型[40.6（33.0，51.8）、35.0（33.3，42.4）、36.1（32.8，47.2）ng/ml，P = 0.601]的9-羟基利培酮稳态血浆浓度几何均值也无差异。包括CYP2D6基因型、性别和年龄的多元回归分析显示，利培酮稳态血浆浓度与CYP2D6突变等位基因数量相关（标准化偏相关系数（β）= 0.540，P < 0.001），9-羟基利培酮稳态血浆浓度与CYP2D6突变等位基因数量相关（标准化β = 0.244，P = 0.038），活性部分（标准化β = 0.257，P = 0.027）与年龄相关。
这些发现表明，MDR-1变异与利培酮或9-羟基利培酮的稳态血浆浓度无关，但CYP2D6基因型和年龄是这些浓度的决定因素。
