title: Human plasma concentrations of herbicidal carbamate molinate extrapolated from the pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and physiologically based pharmacokinetic modeling.
abstract: To predict concentrations in humans of the herbicidal carbamate molinate, used exclusively in rice cultivation, a forward dosimetry approach was carried out using data from lowest-observed-adverse-effect-level doses orally administered to rats, wild type mice, and chimeric mice with humanized liver and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated hydroxylation of molinate, but rat livers additionally produced molinate sulfoxide and an unidentified metabolite. Adjusted animal biomonitoring equivalents for molinate and its primary sulfoxide from animal studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. The slower disposition of molinate and accumulation of molinate sulfoxide in humans were estimated by modeling after single and multiple doses compared with elimination in rodents. The results from simplified PBPK modeling in combination with chimeric mice with humanized liver suggest that ratios of estimated parameters of molinate sulfoxide exposure in humans to those in rats were three times as many as general safety factor of 10 for species difference in toxicokinetics. Thus, careful regulatory decision is needed when evaluating the human risk resulting from exposure to low doses of molinate and related carbamates based on data obtained from rats.
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Masanao
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Sayako
authors.initials: S
authors.lastname: Nishiyama
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan. Electronic address: hyamazak@ac.shoyaku.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002678:Chimera; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D008954:Models, Biological; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013454:Sulfoxides / Q000378:metabolism; D013859:Thiocarbamates / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D001381:Azepines; D006540:Herbicides; D013454:Sulfoxides; D013859:Thiocarbamates; C009821:molinate; C553160:molinate sulfoxide
keywords: Allometric scaling; Lowest-observed-adverse-effect level; Physiologically based pharmacokinetic model; Simulation; Transplanted human liver cells