Genetic Polymorphisms on pharmacokinetics and pharmacodynamics of mycophenolate mofetil in Thai kidney transplant patients

Abstract

The objectives of this study were to investigate the influence of genetic polymorphisms on pharmacokinetics and pharmacodynamics of mycophenolate mofetil in 118 Thai kidney transplant patients. Mean age was 45 years old and most patients received concomitant cyclosporine or tacrolimus therapy. Mean daily dose of mycophenolate mofetil was 1211.86±339.10 mg (range 500-2000 mg). Allele frequencies of UGT1A9*1b, UGT1A9 -688T>G, UGT2B7 802C>T, MRP-2 -24C>T, IMPDH1 125G>A, IMPDH1 -106G>A and IMPDH2 3757T>C were 0.49, 0.12, 0.27, 0.23, 0.41, 0.58 and 0.01, respectively. Seventy eight patients (66.10%) had predicted AUC0-12 hr of mycophenolic acid (MPA) within target range (mean 46.59±8.08 mg x h/L). When considering the association of gene polymorphisms and pharmacokinetic parameters, patients with MRP-2 -24C>T variant had a significantly lower predicted MPA AUC0-12 hr than patients with wild-type gene (5.044 and 5.921 mg x h/L/mg/kg, respectively, p-value = 0.008). In addition, the oral clearance of MPA in patients with MRP-2 -24C>T variant was significantly higher than the oral clearance of MPA in patients with wild-type gene (0.150 and 0.120 L/h/kg, respectively, p-value = 0.025). There were no significantly differences of pharmacokinetic parameters among patients with different polymorphisms of UGT1A9*1b, UGT1A9 -688T>G and UGT2B7 802C>T SNPs. For pharmacodynamic parameters, IMPDH activity was determined. Patients with IMPDH1 125G>A variant had a significantly higher IMPDH activity at predose and 2 hour after morning MMF dose than patients with wild-type gene. No differences of IMPDH activity was found among patients with different polymorphisms of IMPDH1 -106G>A and IMPDH2 3757T>C SNPs. In summary, the effects of MRP-2 SNP on pharmacokinetics and IMPDH1 SNP on pharmacodynamics of mycophenolate mofetil were documented. These genotypes may be the factor for dose guiding and outcome monitoring in Thai kidney transplant patients.