title: Comparative metabolism of benfuracarb in in vitro mammalian hepatic microsomes model and its implications for chemical risk assessment.
abstract: In vitro metabolism of benfuracarb in liver microsomes from seven species was studied in order to quantitate species-specific metabolic profiles and enhance benfuracarb risk assessment by interspecies comparisons. Using LC-MS/MS, a total of seven phase-I-metabolites were detected from the extracted chromatograms and six of them were unequivocally identified. Benfuracarb was metabolized via two metabolic pathways, the sulfur oxidation pathway and nitrogen sulfur bond cleavage, yielding carbofuran, which metabolized further. Analysis of the metabolic profiles showed that benfuracarb was extensively metabolized with roughly similar profiles in different species in vitro. In vitro intrinsic clearance rates as well as calculated in vivo hepatic clearances indicated that all seven species metabolize benfuracarb via the carbofuran metabolic pathway more rapidly than the sulfoxidation pathway. The highest interspecies differences in hepatic clearance rate values were for mouse and rat liver microsomes compared to human, i.e. 4.8 and 4.1-fold higher, as illustrated by in vivo hepatic clearance of carbofuran. Overall, there are quantitative interspecies differences in the metabolic profiles and kinetics of benfuracarb biotransformation. These findings illustrate that in vitro studies of benfuracarb metabolite profiles and toxicokinetics are helpful for the proper selection and interpretation of animal models for toxicological evaluation and chemical risk assessment.
authors: Center for Arctic Medicine, Thule Institute, University of Oulu, Finland; Pharmacology and Toxicology Unit, Institute of Biomedicine, P.O. Box 5000, FI-90014 University of Oulu, Oulu, Finland. Electronic address: khaled.megahed@oulu.fi.
authors: Khaled
authors: K
authors: Abass
authors: Petri
authors: P
authors: Reponen
authors: Sampo
authors: S
authors: Mattila
authors: Arja
authors: A
authors: Rautio
authors: Olavi
authors: O
authors: Pelkonen
mesh_terms: D000328:Adult; D000818:Animals; D001572:Benzofurans / Q000378:metabolism* / Q000633:toxicity; D004285:Dogs; D005260:Female; D006801:Humans; D007306:Insecticides / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D011817:Rabbits; D051381:Rats; D018570:Risk Assessment; D013045:Species Specificity; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity
chemical_list: D001572:Benzofurans; D007306:Insecticides; D015091:beta-Alanine; C096128:benfuracarb
keywords: In vitro metabolism; P450; Pesticides; Risk assessment; Toxicokinetics