有机阴离子转运多肽1B1遗传多态性对普伐他汀药动学的影响

Effects of Genetic Polymorphism of OATP1B1 on Pharmacokinetics of Pravastatin

目的初步考察汉族人有机阴离子转运多肽1B1(OATP1B1)的遗传多态性及其对普伐他汀药动学的影响。方法考察180名汉族健康受试者SLCO1B1(OATP1B1的编码基因)的常见单体型(SLCO1B1*1a,SLCO1B1*1b,SLCO1B1*5及SLCO1B1*15),从中选择18名自愿参加且基因型为SLCO1B1*1b/*1b,SLCO1B1*1a/*15,SLCO1B1*1b/*15或SLCO1B1*15/*15的受试者入组药动学研究。分别在给药前及给予40 mg普伐他汀后0.33,0.67,1,1.5,2,3,4,5,6,8 h采集受试者血样至肝素抗凝管中。血浆普伐他汀浓度采用HPLC-UV测定。药动学参数应用WinNonlin 1.5软件中的非房室模型计算。SLCO1B1*1b纯合子组受试者(n=9)和SLCO1B1*15杂合子组受试者(n=8)药动学参数的统计学差异应用SPSS 10.0软件中的Mann-Whitney U检验评价。结果180名汉族人单体型SLCO1B1*1a,SLCO1B1*1b和SLCO1B1*15的发生频率分别为0.294,0.614和0.092,未发现单体型SLCO1B1*5;基因型SLCO1B1*1a/*1a,SLCO1B1*1a/*1b,SLCO1B1*1b/*1b,SLCO1B1*1a/*15,SLCO1B1*1b/*15及SLCO1B1*15/*15的发生频率分别为0.078,0.372,0.372,0.061,0.111及0.006。SLCO1B1*1b纯合子组受试者(n=9)和SLCO1B1*15杂合子组受试者(n=8)的ρmax分别为(116.06±46.22)和(173.36±36.23)μg·L-1,二者存在统计学差异(P=0.011<0.05)。2组受试者的其他药动学参数,如AUC0-8 h(P=0.093>0.05),tmax(P=0.139>0.05),t1/2(P=0.093>0.05)及CL/F(P=0.114>0.05)无统计学差异。值得注意的是,SLCO1B1*15纯合子(n=1)的ρmax和AUC0-8 h在所有受试者中最高,分别为401.76μg·L-1和660.05μg·h·L-1;CL/F最低,为59.60 L·h-1。结论180名汉族人OATP1B1存在遗传多态性,最常见的单体型为SLCO1B1*1b。OATP1B1遗传多态性会对普伐他汀药动学产生影响。服用普伐他汀后,携带SLCO1B1*15的受试者,尤其是SLCO1B1*15纯合子受试者的血药浓度显著高于其他受试者。

OBJECTIVE To investigate the genetic polymorphism of organic anion transporting polypeptide 1B1 （OATP1 B1 ） in Han population and the effects of the genetic polymorphism on the pharmacokinetie profile of pravastatin. METHODS The common haplotypes of SLCO1B1 （the coding gene of OATP1B1 ）, which were reported as SLCO1B1 ^＊1a, SLCO1B1 ^＊1b, SLCO1B1 ^＊5 and SLCO1 B1 ^＊15, were determined in 180 Han healthy subjects, 18 of whom with the genotypes of SLCO1 B1 ^＊1 b/^＊1 b, SLCO1 B1 ^＊1 a/^＊15, SLCO1 B1 ^＊1b/^＊15 or SLCO1 B1 ^＊15/^＊15 were chosen and grouped in the pharmacokinetic study. Serial blood samples were collected into heparinized tubes before dosing and at 0. 33, 0. 67, 1, 1.5, 2, 3, 4, 5, 6 and 8 h after 40 mg pravastatin administration. The plasma pravastatin concentrations were assayed by HPLC-UV method. The phannacokinetic parameters were assessed by a noncompartment model using WinNonlin 1.5 software. The statistical differences of the pharmacokinetic parameters between the SLCO1B1 ^＊1 b homozygous carriers （ n = 9） and the SLCOI B1 ^＊15 heterozygous carriers （ n = 8 ） were determined by Mann-Whitney 13 test using SPSSI0. 0 software. RESULTS The frequencies of SLCOI B1 ^＊1 a, SLCO1 B1 ^＊1b and SLCO1 B1 ^＊15 were 0. 294, 0. 614, 0. 092, respectively. However, no SLCO1 B1 ^＊5 was found. The frequencies of SLCO1 B1^＊1 a/^＊1 a, SLCO1 B1 ^＊1 a/^＊1 b, SLCO1 B1 ^＊1 b/^＊ 1b, SLCO1B1^＊1a/^＊15, SLCO1B1^＊1b/^＊15 and SLCO1B1^＊15/^＊15 were 0.078, 0.372, 0.372, 0.061, 0.111 and 0.006, respectively. It was showed that the values of ρmax were （ 116. 06 ± 46.22） and （ 173.36 ± 36. 23 ） μg · L^-1 in the SLCO1 B1 ^1 b homozygons carriers and the SLCO1 B1 ^＊15 heterozygous carriers, respectively, with significant difference （ P = 0. 011 〈 0. 05 ）. Other pharmacokinetic parameters, such as AUC0-8 h （ P = 0. 093 〉 0.05 ）, tmax （ P = 0, 139 〉 0.05 ）, t1/2 （ P = 0. 093 〉 0. 05 ） and CL/F （ P = 0. 114 〉 0.05 ） , had no significant differences between the two study groups. Strikingly, the ρmax and AUC0-8 h in the SLCO1 B1 ^＊15 homozygous carrier （n = 1 ） , which were 401.76 μg · L^-1 and 660.05 μg · h · L^ -1 , respectively, were the highest, the CL/F which was 59. 60 L · h^ -1 was the lowest among all participants. CONCLUSION There was genetic polymorphism of OATP1B1 in Han population, and the most common haplotype was SLCO1B1^ ＊lb. The pharmacokinetic profile of pravastatin was affected by the genetic polymorphism of OATP1B1. After pravastatin administration, higher concentrations were seen in the SLCOI B 1^ ＊15 carriers, especially the SLCO1 B1 ^＊15 homozygous carrier.