Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone.
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.
Yu
Rong Chun
RC
Center for Occupational and Environmental Health, UCLA School of Public Health, Los Angeles, CA 90095, USA.
Hattis
Dale
D
Landaw
Elliot M
EM
Froines
John R
JR
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
D002074:Butanones; D006588:Hexanones; D009498:Neurotoxins; C005222:methylethyl ketone; C011269:2,5-hexanedione