临床药代动力学：第10讲 药代动力学的种族差异和个体差异

1、药代动力学的种族差异和个体差异药代动力学的种族差异和个体差异给予固定剂量的药物后血药浓度在人群给予固定剂量的药物后血药浓度在人群中的分布中的分布“one-size-fits-all”根据药物基因组学（根据药物基因组学（PGx）分组受试者）分组受试者基因芯片的应用基因芯片的应用影响药代个体差异的体内环节影响药代个体差异的体内环节（吸收、分布、代谢、排泄，（吸收、分布、代谢、排泄，ADME） Drug Transporters in Absorption and Excretion P-glycoprotein Organic anion transporting polypeptides (OA

2、TPs) Molecules in Distribution albumin, A1-acid glycoprotein, and lipoproteins Drug Metabolizing EnzymesCytochromes P450Thiopurine MethyltransferaseN-Acetyl transferases以药物代谢酶为例 代谢酶的活性由基因多态性决定，而基因多态性分布的频率在种族间存在差异细胞色素细胞色素P450酶酶（Cytochrome P450，CYP450) 各CYP450酶参与药物代谢的比例 在白种人，CYP2D6慢代谢者比例较高（7%），原因是存在较高

3、的CYP2D6*4 和 CYP2D6*5分布。亚洲人中CYP2D6*10分布比率较高（50%），携带者CYP2D6酶为中等活性。 在亚洲人中，CYP2C19慢代谢者比例较高（19%），因为CYP2C19*2和CYP2C19*3的高分布。而在白种人中仅发现2%的人携带CYP2C19*2。种族差异Genotype frequencies observed for CYPs in Caucasian, Chinese, Japanese and Korea populationsGeneGenotypeCaucasianChineseJapaneseKoreaCYP2C9*10.890.950.93

4、0.93*20.23000*30.210.050.070.07CYP2C19*10.910.900.810.81*20.260.520.560.45*300.71.61.2*170.330.010.010.01Genotype frequencies observed for CYPs in Caucasian, Chinese, Japanese and Korea populationsGeneGenotypeCaucasianChineseJapaneseKoreaCYP2D6*10.550.500.610.51*20.270.280.260.30*30.05000*40.2900.01

5、0*50.030.120.130.15*100.080.730.520.67CYP 3A5*1*100.070.050.06*1*30.080.410.340.37*3 *30.850.520.610.57*1B/C AND *3*30.07000肠道转运蛋白肠道转运蛋白P-gp, BCRP, MRP1, OATP3PEPT1脑中转运蛋白脑中转运蛋白P-gp, OAT3, OATP-A, MRP1, MRP3肝脏转运蛋白肝脏转运蛋白P-gp, MRP2, BCRP, MDR3, MRP1OCT1, OATP-C, OATP-B, OATP8, OAT2肾脏转运蛋白肾脏转运蛋白P-gp, OAT

6、4PEPT2存在于人体各处的转运蛋白存在于人体各处的转运蛋白转运蛋白转运蛋白存在组织存在组织底物底物抑制剂抑制剂P-gpIntestine, liver, kidney, brain, placenta, adrenal, testesDigoxin loperamide cyclosporine A talinolol vinblastine indinavir mitoxantrone danorubicin topotecanCyclosporine A Verapamil Ketoconazole tacrolimus, elacridar (GF120918)BCRPIntestin

7、e, liver, breast, placentaMitoxantrone danorubicin topotecan coxorubicineCyclosporine A elacridar fumitremorgin cMRP1Intestine, liver, kidney, brainvinblastine Indinavir adefovir danorubicin topotecanNeed to add inhibitors hereChoudhuri & Klaassen (2006) International Journal of Toxicology, 25; 231-

8、259转运蛋白的底物和抑制剂The allele frequency of the most common nonsynonymous for European American and Asians ProteinEuropean American (%)Asians (%)Influx transportersOCT1Val408Met (40.2)Val408Met (23.8)OCT2Ala270Ser(15.8)Ala270Ser(8.6)OAT3Val448Ile(1.3)Ile305Phe(3.5)OAT4Arg48STOP(2.2)OATP1A2Glu170Asp(1.9)Le

9、u573Val(37.5)OATP2B1Gln312Arg(10.8)Gln312Arg(38.9)MATE2-kArg393STOP(0.9)Gln312Arg(38.9)OCT, 阳离子转运蛋白; OAT, 阴离子转运多肽; MATE, 多药和毒素外排蛋白 The allele frequency of the most common nonsynonymous for European American and Asians ProteinEuropean American (%)Asians (%)Efflux transportersP-gpAla893Ser(43.8)Ala893

10、Ser(45.0)MRP1Val353Met(0.5)Ala989Thr(0.5)MRP2Val417Ile(17.0)Val417Ile(11.7)MRP3Ser346Phe(2.5)Gly11Asp(0.8)BCRPGln141Lys(8.1)Gln141Lys(40.8)P-gp, P-糖蛋白; MRP, 多药耐药相关蛋白; BCRP, 乳腺癌耐药蛋白实例分析实例分析利培酮种族差异利培酮种族差异 2mg 片剂片剂ParameterCaucasianChinesen2523Cmax(gL1)13.12（5.95，31.51）15.01（7.74，30.6）tmax(h)1.00（0.50，

11、3.00）1.01（0.50，4.00）AUC0t(gL1h)43.72（14.9，188.35）70.97（25.84，338.34）AUC(gL1h)46.01（16.69，195.27）72.74（26.41，342.26）t1/2(h)3.6（1.30，5.70）5.55（1.77，22.18）Geometric mean (CV%) 利培酮个体差异利培酮个体差异Mean values for risperidone plasma concentration over time in subjects expressing CYP2D6*1/*1 ( n =5) , *1/*10 (

12、n = 12) ,*10/*10( n = 6) after single administration of 2 mg Risperidone. Journal of Clinical Pharmacology, 2010, 50(6), 659-66Mean values for risperidone AUC(0 - ) in subjects expressing CYP2D6*1/*1 ( n =5) , *1/*10 ( n = 12) ,*10/*10( n = 6) after single administration of 2 mg Risperidone.248.264.

13、830.6Summary of the pharmacokinetic parameters of Active Moiety between the CYP2D6*10/*10/CYP3A5*3/*3 carries and other CYP2D6 EMs CYP2D6*10/*10 and CYP3A5*3/*3Other CYP2D6 EMP Valuenn = 4n = 19Cmax (ngml-1)36.92 (4.65, 69.18) 23.17 (19.87, 26.28)0.027Tmax (h)0.75 (0.42, 1.07)1.71 (1.15, 2.27)0.002A

14、UC(0-last) (nghml-1)647.66 (-45.79, 1341.11)328.09 (295.09, 361.09)0.002AUC(0-infinity)(nghml-1)674.87 (-28.00, 1377.74)340.64 (307.03, 374.24)0.002CL/F (h-1)3.69 (1.30, 6.09)6.05 (5.59, 6.51)0.002利培酮个体差异利培酮个体差异结论结论: 在中国人群中，CYP2D6*10 决定了利培酮的血药浓度水平，且不同基因型间差异显著（2-8倍） 对于利培酮总活性物，同时携带CYP2D6*10/*10和CYP3A5

15、*3/*3基因型者与其他受试者相比，AUC(0-last)高 97%， Cmax高 59% （p 0.05） 利培酮药代动力学试验应充分考虑CYP450代谢酶基因型的影响。兰索拉唑种族差异兰索拉唑种族差异 30mg 胶囊胶囊 ParameterCaucasianChineseJapanesen272424Age (years)24.484.534.93.021.401.3Weight (kg)75.016.465.37.163.347.0Height (cm)177.786.417010172.686.1Sex (m/f)25m, 3f24m24mCmaxng/ml758.09372.09799.2257.5949.2361.68Tmaxh1.860.882.151.031.6250.6797AUC0-lasth.ng/ml1842.281501.152468.0874.72168.91142.52AUC0-h.ng/ml1862.781517.842559.8