Furathiocarb is a carbamate insecticide detected in ecosystems. Its main metabolite carbofuran ha... more Furathiocarb is a carbamate insecticide detected in ecosystems. Its main metabolite carbofuran has been alluded to affect birth outcomes and disturb hormone levels in humans. The metabolism of furathiocarb in humans has not been characterized. The metabolism studies were performed using hepatic microsomes from ten donors and fifteen human cDNA-expressed CYPs. The initial screening and identification of the metabolites were performed by LC-TOF. Quantifications and fragmentations were performed by LC/MS-MS. Furathiocarb was metabolized to eight phase I metabolites via two general pathways, carbofuran metabolic pathway and furathiocarb oxidation pathway. Six metabolites in the carbofuran metabolic pathway (carbofuran, 3-hydroxycarbofuran, 3-ketocarbofuran, 3-keto-7-phenolcarbofuran, 3-hydroxy-7-phenolcarbofuran, and 7-phenolcarbofuran) were identified with the help of authentic standards. The two unidentified metabolites in the furathiocarb oxidation pathway are probably hydroxylated and sulfoxidated derivatives of furathiocarb. The carbofuran metabolic pathway was more predominant than the furathiocarb oxidation pathway, ratios ranged from 24- to 115-fold in a 10-donor panel of hepatic microsomes. On the basis of recombinant CYP studies, the carbofuran pathway was dominated by CYP3A4 (95.9%); contributions by CYP1A2 (1.3%) and CYP2B6 (2.0%) were minor. The minor furathiocarb oxidation pathway was catalyzed by CYP2C19 and CYP2D6 (hydroxylated/sulfoxidated metabolite A) and by CYP3A5, CYP3A4 and CYP2A6 (metabolite B). High and significant correlation between carbofuran metabolic pathway and CYP3A4 marker activities (midazolam-1'-hydroxylation and omeprazole-sulfoxidation) were observed. Ketoconazole, a CYP3A4-inhibitor, inhibited the carbofuran pathway by 32–86% and hydroxylated/sulfoxidated metabolite-B formations by 41–62%. The data suggest that in humans, the carbofuran metabolic pathway is dominant, and CYP3A4 is the major enzyme involved. These results provide useful scientific information for furathiocarb risk assessment in humans.
"Currently public concern about the impact of pesticides, including fungicides, on human hea... more "Currently public concern about the impact of pesticides, including fungicides, on human health is greater than ever before. Pesticides are essential in agricultural production, but they constitute a potential risk to humans who are exposed to them directly through various ways and indirectly through the diet. Accordingly, the health risk assessment of pesticides is of utmost importance for the protection of human health. Risk assessment needs reliable scientific information and one source of information is the characterization of the metabolic factors and toxicokinetics. Indeed, quantitative toxicokinetic data in humans are needed for human risk assessment to make reliable comparisons between individuals or between species. Because humans cannot be used as study subjects except in occasional circumstances, we have to rely upon in vitro experiments, human-derived techniques and in vitro – in vivo predictions as well. In the usual course of events, the more we know about pesticides in terms of their metabolic characteristic in vitro, the better we will be in extrapolation of in vitro and animal studies into human risk assessment. Cytochrome P450 enzymes are important in the metabolism of various endogenous substrates as well as a wide range of xenobiotics. The metabolism may results in activation and/or detoxification reactions. Basically, metabolic factors such as metabolic routes, identification of the major and minor metabolites, metabolite stability, metabolizing enzymes, interindividual variability, interspecies differences and the inhibitory interactions are providing important quantitative data for chemical risk assessment. In this review we will briefly describe the in vitro techniques used to study in vitro metabolism and interactions, summarize the metabolic and kinetic properties of selected fungicides and provide an example from our own studies about how to apply current techniques to obtain relevant data for risk assessment."
This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 ... more This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) of oral ketamine by 2.4-fold (P < 0.001), whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0-∞) to ketamine AUC(0-∞) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than th...
Furathiocarb is a carbamate insecticide detected in ecosystems. Its main metabolite carbofuran ha... more Furathiocarb is a carbamate insecticide detected in ecosystems. Its main metabolite carbofuran has been alluded to affect birth outcomes and disturb hormone levels in humans. The metabolism of furathiocarb in humans has not been characterized. The metabolism studies were performed using hepatic microsomes from ten donors and fifteen human cDNA-expressed CYPs. The initial screening and identification of the metabolites were performed by LC-TOF. Quantifications and fragmentations were performed by LC/MS-MS. Furathiocarb was metabolized to eight phase I metabolites via two general pathways, carbofuran metabolic pathway and furathiocarb oxidation pathway. Six metabolites in the carbofuran metabolic pathway (carbofuran, 3-hydroxycarbofuran, 3-ketocarbofuran, 3-keto-7-phenolcarbofuran, 3-hydroxy-7-phenolcarbofuran, and 7-phenolcarbofuran) were identified with the help of authentic standards. The two unidentified metabolites in the furathiocarb oxidation pathway are probably hydroxylated and sulfoxidated derivatives of furathiocarb. The carbofuran metabolic pathway was more predominant than the furathiocarb oxidation pathway, ratios ranged from 24- to 115-fold in a 10-donor panel of hepatic microsomes. On the basis of recombinant CYP studies, the carbofuran pathway was dominated by CYP3A4 (95.9%); contributions by CYP1A2 (1.3%) and CYP2B6 (2.0%) were minor. The minor furathiocarb oxidation pathway was catalyzed by CYP2C19 and CYP2D6 (hydroxylated/sulfoxidated metabolite A) and by CYP3A5, CYP3A4 and CYP2A6 (metabolite B). High and significant correlation between carbofuran metabolic pathway and CYP3A4 marker activities (midazolam-1'-hydroxylation and omeprazole-sulfoxidation) were observed. Ketoconazole, a CYP3A4-inhibitor, inhibited the carbofuran pathway by 32–86% and hydroxylated/sulfoxidated metabolite-B formations by 41–62%. The data suggest that in humans, the carbofuran metabolic pathway is dominant, and CYP3A4 is the major enzyme involved. These results provide useful scientific information for furathiocarb risk assessment in humans.
"Currently public concern about the impact of pesticides, including fungicides, on human hea... more "Currently public concern about the impact of pesticides, including fungicides, on human health is greater than ever before. Pesticides are essential in agricultural production, but they constitute a potential risk to humans who are exposed to them directly through various ways and indirectly through the diet. Accordingly, the health risk assessment of pesticides is of utmost importance for the protection of human health. Risk assessment needs reliable scientific information and one source of information is the characterization of the metabolic factors and toxicokinetics. Indeed, quantitative toxicokinetic data in humans are needed for human risk assessment to make reliable comparisons between individuals or between species. Because humans cannot be used as study subjects except in occasional circumstances, we have to rely upon in vitro experiments, human-derived techniques and in vitro – in vivo predictions as well. In the usual course of events, the more we know about pesticides in terms of their metabolic characteristic in vitro, the better we will be in extrapolation of in vitro and animal studies into human risk assessment. Cytochrome P450 enzymes are important in the metabolism of various endogenous substrates as well as a wide range of xenobiotics. The metabolism may results in activation and/or detoxification reactions. Basically, metabolic factors such as metabolic routes, identification of the major and minor metabolites, metabolite stability, metabolizing enzymes, interindividual variability, interspecies differences and the inhibitory interactions are providing important quantitative data for chemical risk assessment. In this review we will briefly describe the in vitro techniques used to study in vitro metabolism and interactions, summarize the metabolic and kinetic properties of selected fungicides and provide an example from our own studies about how to apply current techniques to obtain relevant data for risk assessment."
This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 ... more This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) of oral ketamine by 2.4-fold (P < 0.001), whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0-∞) to ketamine AUC(0-∞) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than th...
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