Modulation of trichloroethylene in vitro metabolism by different drugs in rats.

ABSTRACT

Trichloroethylene (TCE) is a widely used chemical to which humans are frequently exposed. Toxicological interactions with drugs are among factors having the potential to modulate the toxicity of TCE. The aim of this study was to identify metabolic interactions between TCE and 14 widely used drugs in rat suspended hepatocytes and characterize the strongest using microsomal assays (oxidation and/or glucuronidation). The concentrations of TCE and its metabolites, trichloroethanol (TCOH) and trichloroacetate (TCA), were measured by gas chromatography with injection headspace coupled to mass spectrometry (GC-MS). Results in hepatocyte incubations show that selected drugs can be segregated into four groups group 1 drugs causing no significant interactions (five drugs amoxicillin, carbamazepine, ibuprofen, mefenamic acid and ranitidine); group 2 increasing both TCE metabolites (two drugs naproxen and salicylic acid); group 3 decreasing both TCE metabolites (five drugs acetaminophen, gliclazide, valproic acid, cimetidine and diclofenac) and group 4 affecting only one (two drugs erythromycin and sulphasalazine). Naproxen and salicylic acid (group 2) and acetaminophen, gliclazide and valproic acid (from group 3) presented the strongest interactions (i.e. drugs changing metabolite levels by 50% or more). For group 2 drugs, characterization in rat microsomes confirmed interaction with naproxen only, which was found to partially competitively inhibit TCOH glucuronidation (K(i) = 211.6 µM). For group 3 selected drugs, confirmation was positive only for gliclazide (K(i) = 58 µM for TCOH formation) and valproic acid (K(i) = 1215.8 µM for TCA formation and K(i) = 932.8 µM for TCOH formation). The inhibition was found to be partial non competitive for both drugs. Our results confirm the existence of interactions between TCE and a variety of widely used drugs. Further efforts are undertaken to determine if these interactions are plausible in humans and if they can impact the risk of toxicity of TCE in medicated population.