Effects of uridine diphosphate glucuronosyltransferase 2B7 and 1A7 pharmacogenomics and patient clinical parameters on steady-state mycophenolic acid pharmacokinetics in glomerulonephritis
- 138 Downloads
The role of pharmacogenomics, clinical and demographic parameters in pharmacokinetic predictions was evaluated in patients receiving mycophenolic acid (MPA).
A cohort study design of patients with glomerulonephritis secondary to lupus nephritis and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis was employed. Forty-six patients with lupus nephritis and ANCA vasculitis who were receiving MPA were recruited from the nephrology clinic. The study assessed the relative single and combined roles of genomic, clinical, and demographic characteristics on pharmacokinetic parameters using general linear models. The study focused on polymorphisms in UGT1A7, UGT2B7, and ABCB1/MDR1; all of which have limited data available concerning MPA pharmacokinetics. All patients had pharmacokinetic assessments for MPA and glucuronide metabolites (MPAG, AcMPAG). Genotyping was performed for known variants of UGTs (UGT1A9, UGT1A7, UGT2B7), and multidrug resistance protein (ABCB1/MDR1), involved in MPA disposition. Analyses included univariate and multivariate linear modeling.
In univariate analyses, UGT2B7 heterozygosity (coefficient 0.3508; R 2=0.0873) and UGT1A7 heterozygosity (coefficient 0.3778; R 2=0.0966) predicted increased apparent oral clearance of MPA. UGT1A7 heterozygosity (coefficient −0.4647; R 2 0.0897) predicted lower MPA trough concentrations. In multivariate assessments, higher urinary protein excretion, lower serum creatinine, and increased weight predicted greater apparent oral clearance of MPA (p < 0.0001). White race and higher serum creatinine predicted higher MPA trough concentrations (p < 0.0001). Higher exposure to MPA was predicted by decreased urinary protein excretion and increased serum creatinine.
Clinical and demographic parameters were 2–4 times more important in MPA disposition than genotypes and explained 30–40% of the pharmacokinetic parameters.
KeywordsMycophenolic acid UGT2B7 UGT1A7 ABCB1 MDR1 Glomerulonephritis
We wish to thank Howard McLeod, PharmD for review of and suggestions for this manuscript. This research was funded by the National Institutes of Health 5K23DK64888, General Clinical Research Centers program of the Division of Research Resources, National Institutes of Health RR00046, Clinical and Translational Science Award U54RR024383, and the American College of Clinical Pharmacy Research Institute’s Frontier’s Award.
- 3.Levesque E, Delage R, Benoit-Biancamano MO, Caron P, Bernard O, Couture F, Guillemette C (2007) The impact of UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharmacokinetic profile of mycophenolic acid after a single oral dose in healthy volunteers. Clin Pharmacol Ther 81:392–400CrossRefPubMedGoogle Scholar
- 8.Kuypers DR, Naesens M, Vermeire S, Vanrenterghem Y (2005) The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152 T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clin Pharmacol Ther 78:351–361CrossRefPubMedGoogle Scholar
- 9.Zhang WX, Chen B, Jin Z, Yu Z, Wang X, Chen H, Mao A, Cai W (2008) Influence of uridine diphosphate (UDP)-glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients. Xenobiotica 38:1422–1436CrossRefPubMedGoogle Scholar
- 21.Van Hest RM, Mathot RA, Pescovitz MD, Gordon R, Mamelok RD, van Gelder T (2006) Explaining variability in mycophenolic acid exposure to optimize mycophenolate mofetil dosing: a population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients. J Am Soc Nephrol 17:871–880CrossRefPubMedGoogle Scholar