Comparative effects of fibrates on drug metabolizing enzymes in human hepatocytes.

Purpose: The induction potential of different fibric acid derivatives on human drug metabolizing enzymes was evaluated to help assess the role of enzyme induction on pharmacokinetic drug interactions.

Methods: Effects of gemfibrozil, fenofibric acid, and clofibric acid on expression levels of cytochromes P450 (CYPs) 3A4 and 2C8 and UDP-glucuronyltransferase (UGT) 1A1 were evaluated in primary human hepatocyte cultures. The potential for these fibrates to activate human pregnane X receptor (PXR) also was studied in a cell-based PXR reporter gene assay.

Results: All three fibrates caused increases in mRNA levels of CYP3A4 (2- to 5-fold), CYP2C8 (2- to 6-fold), and UGT1A1 (2- to 3-fold). On average, the effects on CYP3A4 were less than (< or =30% of rifampin), while those on CYP2C8 and UGT1A1 were comparable to or slightly higher than (up to 200% of rifampin) the corresponding effects observed with rifampin (10 microM). Consistent with the mRNA results, all fibrates caused moderate (approximately 2- to 3-fold) increases in CYP3A4 activity (measured by testosterone 6beta hydroxylase), as compared to about a 10-fold increase by rifampin. Significant increases (3- to 6-fold) in amodiaquine N-deethylase (a functional probe for CYP2C8 activity) also were observed with clofibric acid, fenofibric acid, and rifampin, in agreement with the mRNA finding. However, in contrast to the mRNA induction, marked decreases (>60%) in CYP2C8 activity were obtained with gemfibrozil treatment. Consistent with this finding, co-incubation of amodiaquine with gemfibrozil, but not with fenofibric acid, clofibric acid, or rifampin, in human liver microsomes or hepatocytes resulted in significantly decreased amodiaquine N-deethylase activity (IC50 = 80 microM for gemfibrozil, >500 microM for fenofibric or clofibric acid, and >50 microM for rifampin). Similar to rifampin, all three fibrates caused a modest change in the glucuronidation of chrysin, a nonspecific substrate of UGTs. No significant activation on human pregnane X receptor (PXR) was observed with the three fibrates in a PXR reporter gene assay.

Conclusions: In human hepatocytes, both fenofibric acid and clofibric acid are inducers of CYP3A4 and CYP2C8. Gemfibrozil is also an inducer of CYP3A4, but acts as both an inducer and an inhibitor of CYP2C8. In this system, all fibrates are weak inducers of UGT1A1. The enzyme inducing effects of fibrates appear to be mediated via a mechanism(s) other than PXR activation. These results suggest that fibrates may have potential to cause various pharmacokinetic drug interactions via their differential effects on enzyme induction and/or inhibition.