title: Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone.
abstract: Co-exposure to methyl ethyl ketone (MEK) potentiates the neurotoxicity of n-hexane in humans as well as in animals. This effect is associated with increased persistence of 2,5-hexanedione (2,5-HD) in blood, probably due to inhibition of 2,5-HD phase II biotransformation by MEK. There is no previous quantitative toxicokinetic model to describe this interaction. In this study we constructed a toxicokinetic model to depict the inhibition of 2,5-HD metabolism and elimination by MEK. Experimental data on 2,5-HD blood concentrations in rats from a published study were used to estimate model parameters. Three different inhibition mechanisms were evaluated: competitive, uncompetitive, and noncompetitive inhibition. Extrapolation from high to low doses was made to assess the interactive effects of MEK on 2,5-HD beyond experimental conditions. The models developed successfully described the toxicokinetic behavior of 2,5-HD when inhibited by MEK. The competitive inhibition model yielded a much lower estimate for the constant (65.5 mg/l) of 2,5-HD inhibition by MEK than did the uncompetitive and noncompetitive models (403 and 440 mg/l, respectively). The apparent half-life of 2,5-HD appeared to be a linear function of the Michaelis-Menten constant, and 2,5-HD and MEK concentrations in rats. The area under the curve of 2,5-HD in blood of rats was a nonlinear function of 2,5-HD and MEK concentrations in the blood. This study highlights the importance of the interactive effect of MEK on deactivation and elimination of 2,5-HD, and further illustrates the advantage of toxicokinetic modeling to investigate chemical interactions associated with exposure to multiple chemical agents.
authors.affiliation: Center for Occupational and Environmental Health, UCLA School of Public Health, Los Angeles, CA 90095, USA.
authors.forename: Rong Chun
authors.initials: RC
authors.lastname: Yu
authors.forename: Dale
authors.initials: D
authors.lastname: Hattis
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Landaw
authors.forename: John R
authors.initials: JR
authors.lastname: Froines
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002074:Butanones / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006207:Half-Life; D006588:Hexanones / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D009498:Neurotoxins / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002074:Butanones; D006588:Hexanones; D009498:Neurotoxins; C005222:methylethyl ketone; C011269:2,5-hexanedione