Anti-UGT1A9 monoclonal antibody Made to order

The availability of assays that predict the contribution of cytochrome P450 (CYP) metabolism allows for the design of new chemical entities (NCEs) with minimal oxidative metabolism. These NCEs are often substrates of non-CYP drug-metabolizing enzymes (DMEs), such as UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), carboxylesterases (CESs), and aldehyde oxidase (AO). Nearly 30% of clinically approved drugs are metabolized by non-CYP enzymes. However, knowledge about the differential hepatic versus extrahepatic abundance of non-CYP DMEs is limited. In this study, we detected and quantified the protein abundance of eighteen non-CYP DMEs (AO, CES1 and 2, ten UGTs, and five SULTs) across five different human tissues. AO was most abundantly expressed in the liver and to a lesser extent in the kidney; however, it was not detected in the intestine, heart, or lung. CESs were ubiquitously expressed with CES1 being predominant in the liver, while CES2 was enriched in the small intestine. Consistent with the literature, UGT1A4, UGT2B4, and UGT2B15 demonstrated liver-specific expression, whereas UGT1A10 expression was specific to the intestine. UGT1A1 and UGT1A3 were expressed in both the liver and intestine; UGT1A9 was expressed in the liver and kidney; and UGT2B17 levels were significantly higher in the intestine than in the liver. All five SULTs were detected in the liver and intestine, and SULT1A1 and 1A3 were detected in the lung. Kidney abundance was the most variable among the studied tissues, and overall, high interindividual variability (>15-fold) was observed for UGT2B17, CES2 (intestine), SULT1A1 (liver), UGT1A9, UGT2B7, and CES1 (kidney). These differential tissue abundance data can be integrated into physiologically based pharmacokinetic (PBPK) models for the prediction of non-CYP drug metabolism and toxicity in hepatic and extrahepatic tissues.

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 (HNF1 alpha) 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 HNF1 alpha 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). HNF1 alpha 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(CO), 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 HNF1 alpha 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. (C) 2013 Elsevier B.V. All rights reserved.