Genetic polymorphisms of UGT1A8, UGT1A9 and HNF-1α and gastrointestinal symptoms in renal transplant recipients taking mycophenolic acid.

Abstract Mycophenolic acid (MPA), a widely used immunosuppressant, has a complex metabolism that involves a number of enzymes. Some of its metabolites are thought to be the cause of gastrointestinal (GI) side effects. In this study, we investigated whether polymorphisms of UDP-glucuronosyltransferases (UGT1) A8, 1A9, and hepatocyte nuclear factor (HNF1α) genes or pharmacokinetic parameters of mycophenolic acid (MPA) were associated with the severity of GI symptoms in patients receiving MPA therapy. A total of 109 kidney transplant patients taking mycophenolic acid (MPA) derivatives were genotyped for UGT1A8, 1A9 and HNF1α genes. Among these, a total of 15 patients were participants in the pharmacokinetic study. Severity of GI symptoms was assessed using a validated Gastrointestinal Symptom Rating Scale (GSRS). The overall and subscale GSRS scores were measured at 1 week (baseline), 2 weeks, 3 months and 6 months post-transplantation. In the case of the pharmacokinetic study, EC-MPS was administered and a total of nine blood samples were obtained at − 1, 0, 0.5, 1, 2, 4, 6, 8, and 12 h. Genotypes of UGT1A8 were significantly associated with the overall GSRS scores at week 1 (p = 0.02) and week 2 (p = 0.036). Subscales were only statistically significant for constipation at week 1 (p = 0.002) and indigestion at week 2 (p = 0.02), while UGT1A9 was only significant for the constipation at week 1 (p = 0.04). HNF1α genotypes were significantly different at week 1 in the overall GSRS (p = 0.004), and for abdominal pain (p = 0.04), acid reflux (p = 0.036) and constipation subscales (p = 0.04). In addition, abdominal pain was statistically significantly different at 3 months and 6 months after transplantation (p = 0.03 and 0.02, respectively). In the case of the pharmacokinetic study, we have found some correlations between MPA C0 and constipation (p = 0.02) where MPA AUC was correlated with acid reflux (p = 0.02) and constipation (p = 0.012), MPAG CL/F was correlated to acid reflux, indigestion, constipation and the sum of the GSRS scores (p = 0.037, p = 0.032, p = 0.033 and p = 0.04, respectively). Multinomial regression analysis for MPAG CL/F showed a statistical significance for the subscale indigestion and the sum of the GSRS (p = 0.033 and p = 0.037, respectively). Our data suggests that among patients receiving MPA the UGT1A9 alleles might play a role in determining the severity of early GI side effects, while the HNF1α allele appears to be associated with a later effect as well as early side effects. Our data also showed that some kinetic parameters might predict MPA side effects.