P185 Alteration in the intrinsic clearance of CYP2B6 by NAFLD: evidence of the involvement of the metabolic syndrome in variable drug response

Enoch Cobbina , University of Rhode Island, Kingston, RI
Anitha Saravanakumar , Univeristy of Rhode Island, Kingston
Fatemeh Akhlaghi , University of Rhode Island, Kingston, RI
Introduction. Variable drug response due to drug-drug interactions, demographic differences, and genetic polymorphisms have been reported. However, variability in drug response due to disease state remains unclear. We investigated the effect of non-alcoholic fatty liver disease (NAFLD), a disease strongly associated with diabetes and the metabolic syndrome, on the intrinsic clearance of cytochrome (CYP) P450 2B6 drug metabolizing enzyme.

Method. Human livers from 106 donors were obtained from Xenotech LLC (Lenexa, KS) and characterized with respect to demography and histopathology. Using the NASH CRN system (Kleiner et al., 2005) and SAF algorithm (Bedossa et al., 2012), the livers were categorized into NoNAFLD, NAFL (non-alcoholic fatty liver) and NASH (non-alcoholic steatohepatitis). Microsomes were extracted from the human livers and incubated with varying concentrations of bupropion (0 - 2000 uM); and microsomal activity of CYP2B6 determined via the hydroxybupropion pathway using LC-MS/MS. The involvement of metabolic hormones in the intricate relationship between NAFLD, diabetes and CYPs was investigated by measuring the concentrations of amylin (active), c-peptide, insulin and PYY in homogenate of the 106 livers using multiplex immunoassay.

Results. The presence of NAFLD significantly reduced the intrinsic clearance of CYP2B6 (p < 0.018); from 687.65 nL.min-1.mg microsome-1 (NoNAFLD group), to 161.50 nL.min-1.mg microsome-1 and 174.20 nL.min-1.mg microsome-1 in NAFL and NASH groups, respectively. The impact of NAFLD on amylin active, c-peptide and PYY correlated with the CYP2B6 findings. Levels of these metabolic hormones were significantly higher in the NAFLD group compared to the NASH group: c-peptide (p<0.0001), amylin active (p <0.03) and PYY (p<0.0007). The strong association between the presence of diabetes, the metabolic hormones and NAFL, described by a logistic regression model, suggests the existence of an intricate relationship between NAFLD and other components of the metabolic syndrome with consequences on CYP2B6 intrinsic clearance.

Conclusion. NAFLD seems to have intricate relationship with diabetes and is a potential source of variability on CYP2B6 intrinsic clearance, partly via alterations in metabolic hormones. This highlights the need for caution in interpreting the effect of one component of the metabolic syndrome on drug metabolizing enzymes since other components could potentially confound the results.