巯嘌呤甲基转移酶活性对硫唑嘌呤中间代谢物6-巯基嘌呤药动学的影响

Influence of Thiopurine Methyltransferase Activity on Pharmacokinetics of 6-mercaptopurine,Which is the Intermediate Metabolite of Azathioprine

目的通过对硫唑嘌呤中间代谢物6-巯基嘌呤(6-mercaptopurine,6-MP)药动学的研究,初步探讨巯嘌呤甲基转移酶(thiopurine methyltransferase,TPMT)活性对6-MP药动学的影响。方法根据红细胞中TPMT活性,受试者分成高酶活性组[(14.52±2.10)μmol.h-1.L-1RBCs,n=16]和低酶活性组[(7.02±2.44)μmol.h-1.L-1RBCs,n=4]。受试者早晨空腹口服硫唑嘌呤100 mg,8 h动态采集静脉血,HPLC测定血浆中6-MP浓度,采用WinNonlin程序进行房室模型拟合及药动学参数计算。结果:6-MP药动学符合一室模型特点,6-MP血浆浓度较低,高酶活性组和低酶活性组ρmax分别是(0.048 3±0.024 3)和(0.039 1±0.010 8)mg.L-1;两组AUC分别是(0.132 0±0.047 2)和(0.093 2±0.012 5)mg.h.L-1;6-MP半衰期短,分别是(1.09±0.65)和(1.25±1.05)h;6-MP表观分布容积大,两组Vd/F分别是(625.63±258.82)和(949.83±670.27)L。高酶活性组和低酶活性组在tmax和tlag存在显著性差异(P<0.05),而Ka,ρmax,AUC,Ke,t1/2,Vd/F,CL/F等药动学参数无显著性差异(P>0.05)。结论由于6-MP代谢的复杂性及独特的组织分布特性,使得TPMT活性对6-MP药动学的影响变得不明显,目前还不能借助6-MP药动学来推测硫唑嘌呤的治疗效果和毒性情况。

OBJECTIVE To study the influence of thiopurine methyltransferase（TPMT） activity on the pharmacokinetics （PK） of 6-mercaptopurine, which is the intermediate metabolite of azathioprine. METHODS Based on TPMT activity in red blood cells, subjects were divided into two groups： the high activity group [n= 16, TPMT activity was （14.52±2.10） μmol·h^-1·L^-1RBCs] and the low activity group [ n = 4, TPMT activity was （7.02 ± 2.44） μmol·h^-1·L^-1RBCs]. Mter a test dose of 100 mg by oral administration, serial plasma samples were collected in 8 h. Plasma drug concentrations were determined by HPLC, and then were assessed with WinNonlin software to obtain the PK parameters. RESULTS The PK of 6-MP was well described by an one-compartment model. 6-MP plasma concentrations were low, ρmax were （0. 048 3 ± 0.024 3） and （0. 039 1 ± 0.010 8） mg·L^-1 for the high activity group and low activity group, respectively. The AUCs of the high activity group and low activity group were （0.132 0±0.047 2） and （0.093 2±0.012 5） mg·h·L^-1.6-MP rapidly disappeared in 8 h. t1/2 were （1.09 ± 0.65） and （1.25 ± 1.05） h for the high activity group and low activity group. The ratios of Vd to F were （625.63 ± 258.82） and （949.83 ± 670.27） L for the high activity group and low activity group. There were significant differences in tmax and t1ag between the two groups （ P 〈 0.05）. CONCLUSION TPMT activity has no effects on PK of 6-MP, so we can not predict the efficiency and toxicity of AZA from the PK parameters of 6-MP in plasma. Further study should be needed.