Metabolism of carbosulfan II. Human interindividual variability in its in vitro hepatic biotransformation and the identification of the cytochrome P450 isoforms involved |
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| Authors: | Khaled Abass Petri Reponen Sampo Mattila Olavi Pelkonen |
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| Affiliation: | 1. Department of Drug Sciences and Health Products, University of Messina, Viale Annunziata, 98168 Messina, Italy;2. Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, D-55099 Mainz, Germany;3. Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20122 Milan, Italy;4. Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100 Sassari, Italy;5. Department of Chemical and Geological Sciences, University of Cagliari, S.S. 554, 09042 Monserrato, CA, Italy;6. Department of Chemistry and Industrial Chemistry, via Risorgimento 35, 56126 Pisa, Italy;7. Laboratory of “Metals in Medicine” (METMED), Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 3, Sesto Fiorentino, 50019 Firenze, Italy;1. Cleveland Clinic Neurological Institute, Cleveland, OH, United States;2. University of Pittsburgh Department of Neurology, Pittsburgh, PA, United States;3. Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States;1. Department of Pediatric Research, Oslo University Hospital, University of Oslo, Norway;2. Department of Neonatology, Women & Children''s Division, Oslo University Hospital, Rikshospitalet, Oslo, Norway;3. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway |
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| Abstract: | This study aims to characterize interindividual variability and individual CYP enzymes involved in the in vitro metabolism of the carbamate insecticide carbosulfan. Microsomes from ten human livers (HLM) were used to characterize the interindividual variability in carbosulfan activation. Altogether eight phase I metabolites were analyzed by LC–MS. The primary metabolic pathways were detoxification by the initial oxidation of sulfur to carbosulfan sulfinamide (‘sulfur oxidation pathway’) and activation via cleavage of the nitrogen sulfur bond (N–S) to give carbofuran and dibutylamine (‘carbofuran pathway’). Differences between maximum and minimum carbosulfan activation values with HLM indicated nearly 5.9-, 7.0, and 6.6-fold variability in the km, Vmax and CLint values, respectively. CYP3A5 and CYP2B6 had the greatest efficiency to form carbosulfan sulfinamide, while CYP3A4 and CYP3A5 were the most efficient in the generation of the carbofuran metabolic pathway. Based on average abundances of CYP enzymes in human liver, CYP3A4 contributed to 98% of carbosulfan activation, while CYP3A4 and CYP2B6 contributed 57 and 37% to detoxification, respectively. Significant correlations between carbosulfan activation and CYP marker activities were seen with CYP3A4 (omeprazole sulfoxidation), CYP2C19 (omeprazole 5-hydroxylation) and CYP3A4 (midazolam 1′-hydroxylation), displaying r2 = 0.96, 0.87 and 0.82, respectively. Activation and detoxification pathways were inhibited by ketoconazole, a specific CYP3A4 inhibitor, by 90–97% and 47–94%, respectively. Carbosulfan inhibited relatively potently CYP3A4 and moderately CYP1A1/2 and CYP2C19 in pooled HLM. These results suggest that the carbosulfan activation pathway is more important than the detoxification pathway, and that carbosulfan activation is predominantly catalyzed in humans by CYP3A4. |
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