AcylMPAG Plasma Concentrations and Mycophenolic Acid-Related Side Effects in Patients Undergoing Renal Transplantation Are Not Related to the UGT2B7-840G>A Gene Polymorphism

Abstract

Mycophenolic acid (MPA) is metabolized primarily by glucuronidation to form the biologically inactive 7-O-glucuronide conjugate (MPAG), which is the major urinary excretion product. MPA is also converted to acyl-glucuronide metabolite (AcylMPAG), which has been suggested to be involved in the generation of MPA-related adverse events such as diarrhea or leucopenia. This conversion of MPA to AcylMPAG is catalyzed by UDP-glucuronosyltransferase 2B7 (UGT2B7). We studied the impact of the -840G>A polymorphisms in the UGT2B7 gene on the pharmacokinetics of AcylMPAG. We also investigated whether the plasma concentrations of AcylMPAG are correlated with MPA-related toxicity to further evaluate its potential clinical significance. In a randomized, controlled trial, comparing fixed-dose mycophenolate mofetil (MMF) with concentration-controlled MMF therapy, patients undergoing renal transplantation were treated with a calcineurin inhibitor, MMF, and corticosteroids. Informed consent was obtained from 332 patients for genotyping. In all patients, blood samples were drawn (three samples within the first 2 hours after administration) on Day 3, Day 10, Week 4, and Months 3, 6, and 12 to measure MPA and AcylMPAG plasma concentrations. The pharmacokinetics of AcylMPAG were correlated with the -840G>A single nucleotide polymorphism (SNP) in the UGT2B7 gene. Heterozygosity for the -840G>A SNP in the UGT2B7 gene was found in 145 patients (145 of 332 [44%]) and 93 (93 of 332 [28%]) patients were homozygous for the -840G>A allele. No difference was found in the dose-normalized AcylMPAG trough (C0) levels and dose-normalized AcylMPAG areas under the concentration-time curve (AUCs) at each visit between carriers and noncarriers of the -840G>A SNP. Also, metabolic ratios, expressed as AcylMPAG/MPA and AcylMPAG/MPAG, were not related to UGT2B7 genotype. The dose-normalized AcylMPAG-C0 and AcylMPAG AUC were higher in the cyclosporine-treated group compared with the tacrolimus-treated patients at each visit. There was no difference in AcylMPAG concentrations (trough or AUC) or AcylMPAG/MPAG ratio between patients with compared with patients without diarrhea. None of the -840G>A UGT2B7 SNPs was disproportionately present among the patients with diarrhea. There was a higher incidence of diarrhea in tacrolimus-treated patients [26 of 163 (16.0%)] compared with cyclosporine-treated individuals [five of 51 (9.8%)], although AcylMPAG concentrations were lower in tacrolimus-treated patients. In this study, we have found no influence of the -840G>A UGT2B7 SNP on AcylMPAG exposure in patients undergoing renal transplantation. There also was no association between this variant genotype and the incidence of diarrhea or leucopenia, two adverse events for which a role for AcylMPAG has been suggested.

New Insights Into the Pharmacokinetics and Pharmacodynamics of the Calcineurin Inhibitors and Mycophenolic Acid: Possible Consequences for Therapeutic Drug Monitoring in Solid Organ Transplantation

“…45,220 Finally, whether a patient is treated with cyclosporine or tacrolimus might have implications for the pharmacokinetics of the glucuronide metabolites of MPA as well. Dosenormalized AcMPAG exposure was reported to be higher in cyclosporine-versus tacrolimus-treated patients, 180,203,221 and as this MPA metabolite is pharmacologically active, this finding might be clinically relevant.…”

“…In healthy volunteers, UGT2B7*2/*2 individuals had a significantly higher MPA AUC 0-12 than UGT2B7*1/*1 individuals, 175 but no significant impact of this polymorphism was found in renal allograft recipients. 173,174,180 Of note, 1 study linked the UGT2B7 haplotype to AcMPAG exposure in sirolimus-treated patients, 173 but this could not be confirmed in CNI-treated patients. 180 Two studies suggested a potential impact of the C-24T SNP in the 5# untranslated region of the gene encoding MRP2 on MPA pharmacokinetics.…”

“…First, there is a clear association between MPA exposure and efficacy, defined as the prevention of acute rejection. [2][3][4][5][127][128][129][130][131][132] Second, the pharmacokinetics of MPA display a high interpatient variability, 130,133 and over the years, numerous factors contributing to this high variability, including renal [133][134][135][136][137][138][139][140] and hepatic impairment, 133 [163][164][165][166][167][168][169][170], and genetic polymorphisms, [171][172][173][174][175][176][177][178][179][180][181] have been identified (Table 1). On the other hand, the lack of a clear relationship between MPA exposure and drug-related toxicity raises doubts about the usefulness of MPA TDM in clinical practice.…”

A New Functional CYP3A4 Intron 6 Polymorphism Significantly Affects Tacrolimus Pharmacokinetics in Kidney Transplant Recipients

“…A pharmacogenetic substudy was started in parallel. Findings on the roles of genetic polymorphisms in the UGT1A9 (UDP glucuronosyltransferase 1 family, polypeptide A9) gene for mycophenolate mofetil (16 ), the UGT2B7 (UDP glucuronosyltransferase 2 family, polypeptide B7) gene for acyl-glucuronide mycophenolic acid (17 ), and CYP3A5/ABCB1 for Tac exposure and acute rejection (18 ) in the FDCC study have previously been published. Patients provided separate written informed consent for the substudy.…”

Role and Clinical Consequences of HumanUDP‐Glucuronosyltransferases

“…Recent investigations evaluating the potential contribution of UGT polymorphisms to adverse events of MPA revealed that polymorphism in the UGT2B7 promoter region −840G>A was found not to be associated with the incidence of leucopenia or diarrhea [114]. However, in a pilot study in pediatric kidney transplant recipients, Prausa et al .…”