藥代動力學的種族差異和個體差異

1、藥代動力學的種族差異和個體差異1給予固定劑量的藥物后血藥濃度在人群中的分布2“one-size-fits-all”3根據(jù)藥物基因組學（PGx）分組受試者4基因芯片的應用5影響藥代個體差異的體內(nèi)環(huán)節(jié)（吸收、分布、代謝、排泄，ADME）Drug Transporters in Absorption and Excretion P-glycoprotein Organic anion transporting polypeptides (OATPs)Molecules in Distribution albumin, A1-acid glycoprotein, and lipoproteinsDru

2、g Metabolizing EnzymesCytochromes P450Thiopurine MethyltransferaseN-Acetyl transferases6以藥物代謝酶為例 代謝酶的活性由基因多態(tài)性決定，而基因多態(tài)性分布的頻率在種族間存在差異7細胞色素P450酶（Cytochrome P450，CYP450) 各CYP450酶參與藥物代謝的比例8在白種人，CYP2D6慢代謝者比例較高（7%），原因是存在較高的CYP2D6*4 和 CYP2D6*5分布。亞洲人中CYP2D6*10分布比率較高（50%），攜帶者CYP2D6酶為中等活性。在亞洲人中，CYP2C19慢代謝者比例較高

3、（19%），因為CYP2C19*2和CYP2C19*3的高分布。而在白種人中僅發(fā)現(xiàn)2%的人攜帶CYP2C19*2。種族差異9Genotype frequencies observed for CYPs in Caucasian, Chinese, Japanese and Korea populationsGeneGenotypeCaucasianChineseJapaneseKoreaCYP2C9*10.890.950.930.93*20.23000*30.210.050.070.07CYP2C19*10.910.900.810.81*20.260.520.560.45*300.71.61.

4、2*170.330.010.010.0110Genotype frequencies observed for CYPs in Caucasian, Chinese, Japanese and Korea populationsGeneGenotypeCaucasianChineseJapaneseKoreaCYP2D6*10.550.500.610.51*20.270.280.260.30*30.05000*40.2900.010*50.030.120.130.15*100.080.730.520.67CYP 3A5*1*100.070.050.06*1*30.080.410.340.37*

5、3 *30.850.520.610.57*1B/C AND *3*30.0700011腸道轉運蛋白P-gp, BCRP, MRP1, OATP3PEPT1腦中轉運蛋白P-gp, OAT3, OATP-A, MRP1, MRP3肝臟轉運蛋白P-gp, MRP2, BCRP, MDR3, MRP1OCT1, OATP-C, OATP-B, OATP8, OAT2腎臟轉運蛋白P-gp, OAT4PEPT2存在于人體各處的轉運蛋白12轉運蛋白存在組織底物抑制劑P-gpIntestine, liver, kidney, brain, placenta, adrenal, testesDigoxin lo

6、peramide cyclosporine A talinolol vinblastine indinavir mitoxantrone danorubicin topotecanCyclosporine A Verapamil Ketoconazole tacrolimus, elacridar (GF120918)BCRPIntestine, liver, breast, placentaMitoxantrone danorubicin topotecan coxorubicineCyclosporine A elacridar fumitremorgin cMRP1Intestine,

7、liver, kidney, brainvinblastine Indinavir adefovir danorubicin topotecanNeed to add inhibitors hereChoudhuri & Klaassen (2006) International Journal of Toxicology, 25; 231-259轉運蛋白的底物和抑制劑13The allele frequency of the most common nonsynonymous for European American and Asians ProteinEuropean American

8、(%)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)Leu573Val(37.5)OATP2B1Gln312Arg(10.8)Gln312Arg(38.9)MATE2-kArg393STOP(0.9)Gln312Arg(38.9)OCT, 陽離子轉運蛋白; OAT, 陰離子轉運多肽; MATE, 多藥和毒素

9、外排蛋白 14The allele frequency of the most common nonsynonymous for European American and Asians ProteinEuropean American (%)Asians (%)Efflux transportersP-gpAla893Ser(43.8)Ala893Ser(45.0)MRP1Val353Met(0.5)Ala989Thr(0.5)MRP2Val417Ile(17.0)Val417Ile(11.7)MRP3Ser346Phe(2.5)Gly11Asp(0.8)BCRPGln141Lys(8.1)

10、Gln141Lys(40.8)P-gp, P-糖蛋白; MRP, 多藥耐藥相關蛋白; BCRP, 乳腺癌耐藥蛋白15實例分析16利培酮種族差異 2mg 片劑ParameterCaucasianChinesen2523Cmax(gL1)13.12（5.95，31.51）15.01（7.74，30.6）tmax(h)1.00（0.50，3.00）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.

11、70）5.55（1.77，22.18）Geometric mean (CV%) 17 利培酮個體差異Mean values for risperidone plasma concentration over time in subjects expressing CYP2D6*1/*1 ( n =5) , *1/*10 ( n = 12) ,*10/*10( n = 6) after single administration of 2 mg Risperidone. Journal of Clinical Pharmacology, 2010, 50(6), 659-6618Mean val

12、ues 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.248.264.830.619Summary of the pharmacokinetic parameters of Active Moiety between the CYP2D6*10/*10/CYP3A5*3/*3 carries and other CYP2D6 EMs CY

13、P2D6*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)0.002AUC(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

14、, 374.24)0.002CL/F (h-1)3.69 (1.30, 6.09)6.05 (5.59, 6.51)0.00220利培酮個體差異結論: 在中國人群中，CYP2D6*10 決定了利培酮的血藥濃度水平，且不同基因型間差異顯著（2-8倍） 對于利培酮總活性物，同時攜帶CYP2D6*10/*10和CYP3A5*3/*3基因型者與其他受試者相比，AUC(0-last)高 97%， Cmax高 59% （p 0.05）利培酮藥代動力學試驗應充分考慮CYP450代謝酶基因型的影響。21蘭索拉唑種族差異 30mg 膠囊 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/ml1862.781517.842559.88