Toxicokinetic interactions between orally ingested chlorzoxazone and inhaled acetone or toluene in male volunteers

The aim of this study was to examine if the drug chlorzoxazone has any infl uence on the toxicokinetics of acetone and toluene. Chlorzoxazone is mainly metabolized by the same enzyme (Cytochrome P450 2E1) as ethanol and many o ther organic solvents. Ten male volunteers were exposed to solvent vapor (2 h, 50 watt) in an exposure chamber. Each subject was exposed to acetone on ly (250 ppm), acetone + chlorzoxazone, toluene (50 ppm) only, toluene + chl orzoxazone, and chlorzoxazone only. Chlorzoxazone (500 mg) was taken as two tablets 1 h prior to solvent exposure. Samples of blood, urine and exhaled air were collected before, during and until 20 h post exposure. The sample s were analyzed by head-space gas chromatography (acetone and toluene) and high-performance liquid chromatography (chlorzoxazone, 6-hydroxychlorzoxazo ne and hippuric acid). The time-concentration curves of acetone and toluene in blood were fitted to one- and four-compartment toxicokinetic models, re spectively. Intake of chlorzoxazone was associated with slight but signific ant increases in the area under the blood concentration-time curve (AUC) an d steady state concentration of acetone in blood, along with non significan t tendencies to an increased half time in blood and an increased AUC in uri ne. Except for a delayed excretion of hippuric acid in urine, no effects on the toluene toxicokinetics were seen after chlorzoxazone treatment. Small increases in chlorzoxazone plasma levels were seen after exposure compared to chlorzoxazone alone. These interactions, although statistically signific ant, seem to be small compared to the interindividual variability on metabo lism and toxicokinetics.