Department of Pharmacy Practice Administration and Research, School of Pharmacy, Marshall University, Huntington, West Virginia, USA.
Transplantation Immunosuppressive Pharmacology Research Program, Translational Pharmacology Research Core, Buffalo, New York, USA.
J Clin Pharmacol. 2021 Dec;61(12):1592-1605. doi: 10.1002/jcph.1932. Epub 2021 Jul 20.
Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is mediated by the multidrug resistance-associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes -24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross-sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC . The wild-type haplotype ABCC2 CGC had greater mycophenolic acid AUC (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine-mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment.
霉酚酸表现出显著的个体间药代动力学变异性，这归因于多种因素，包括种族、性别、同时使用的药物以及霉酚酸葡萄糖醛酸代谢物通过肠肝循环转化为霉酚酸。这种肠肝循环的转化由多药耐药相关蛋白 2（ABCC2）介导。本研究在 147 例接受霉酚酸和钙调磷酸酶抑制剂联合治疗的稳定肾移植受者中，调查了 ABCC2 单倍型与霉酚酸药代动力学的关系。在接受霉酚酸和他克莫司或环孢素治疗的稳定受者的前瞻性、横断面药代动力学研究中，评估了 ABCC2 基因型-24C>T（rs717620）、1249C>T（rs2273697）和 3972C>T（rs3740066）的作用。使用 THESIAS（v.3.1）计算霉酚酸药代动力学参数与 ABCC2 单倍型的表型关联。确定了 4 种频率大于 10%的 ABCC2 单倍型（H1：CGC[野生型]、H9：CGT、H2：CAC、H12：TGT）。种族或性别对单倍型频率没有影响。霉酚酸清除率（L/h）、霉酚酸 AUC（mg·h/L）和霉酚酸葡萄糖醛酸与 AUC 的比值的药代动力学参数与 ABCC2 单倍型有显著关联。野生型 ABCC2 CGC 单倍型的霉酚酸 AUC 较大（P=0.017）、清除率较慢（P=0.013）、霉酚酸葡萄糖醛酸与 AUC 的比值较低（P=0.047），与功能降低的 ABCC2 CGT 单倍型相比。这些差异在同时接受他克莫司治疗的患者中最为明显。环孢素-霉酚酸方案没有发现表型关联。ABCC2 单倍型的变异导致霉酚酸暴露不足，并影响基于同时使用的钙调磷酸酶抑制剂治疗的药代动力学表型的个体间变异性。
