Interactions of some heterocyclic compounds with hepatic microsomal cytochromes P-450.

This study has investigated the interactions of a number of methylenedioxy compounds and some substituted benzimidazoles with hepatic microsomal cytochrome P450. Various substituted benzimidazoles were found to bind to rat hepatic microsomal cytochrome P-450, eliciting the formation of different types of binding spectra. A series of 2-n-alkylbenzimidazoles produced either Type I or Type RI binding spectra and these compounds inhibited monooxygenase reactions, Several methylenedioxy compounds elicited the formation of methylenedioxy metabolite-cytochrome P-450 complexes in the presence of either NADPH and oxygen or cumene hydroperoxide in vitro. Methylenedioxy metabolites were bound to the haem iron of cytochrome P-450 and the resultant complexes were less stable in the oxidized (Fe[3+]) than the reduced (Fe[2+]) state. Oxidized isosafrole metabolite-cytochrome P-450 complexes formed in vivo following the administration of isosafrole to rats were readily dissociated in vitro by the addition of certain substrates of the monooxygenase system. Such substrates were typically lipophilic and had a high affinity for the Type I binding site of cytochrome P-450, An apparent increase in cytochrome P-450 levels and enhanced cytochrome P-450-mediated enzyme activities were observed after the time-dependent dissociation had occurred. When hepatic microsomes from rats which received isosafrole in vivo were subjected to sodium dodecyl sulphate polyacrylamide gel electrophoresis, a protein of 54,000 molecular weight was found to be induced. This protein was identified as a haemoprotein and had an electrophoretic mobility different from the proteins preferentially induced by either phenobarbitone or 20-methylcholanthrene treatment. Both the isosafrole-induced protein and the isosafrole metabolite-cytochrome P-450 complex were observed in microsomal preparations from rats which had received phenobarbitone and isosafrole or 20-methylcholanthrene and isosafrole, Isosafrole-related material was also found to be apparently irreversibly bound to rat and mouse proteins following the administration of [o-[14]C] isosafrole in vivo

Interactions of some heterocyclic compounds with hepatic microsomal cytochromes P-450.

This study has investigated the interactions of a number of methylenedioxy compounds and some substituted benzimidazoles with hepatic microsomal cytochrome P450. Various substituted benzimidazoles were found to bind to rat hepatic microsomal cytochrome P-450, eliciting the formation of different types of binding spectra. A series of 2-n-alkylbenzimidazoles produced either Type I or Type RI binding spectra and these compounds inhibited monooxygenase reactions, Several methylenedioxy compounds elicited the formation of methylenedioxy metabolite-cytochrome P-450 complexes in the presence of either NADPH and oxygen or cumene hydroperoxide in vitro. Methylenedioxy metabolites were bound to the haem iron of cytochrome P-450 and the resultant complexes were less stable in the oxidized (Fe[3+]) than the reduced (Fe[2+]) state. Oxidized isosafrole metabolite-cytochrome P-450 complexes formed in vivo following the administration of isosafrole to rats were readily dissociated in vitro by the addition of certain substrates of the monooxygenase system. Such substrates were typically lipophilic and had a high affinity for the Type I binding site of cytochrome P-450, An apparent increase in cytochrome P-450 levels and enhanced cytochrome P-450-mediated enzyme activities were observed after the time-dependent dissociation had occurred. When hepatic microsomes from rats which received isosafrole in vivo were subjected to sodium dodecyl sulphate polyacrylamide gel electrophoresis, a protein of 54,000 molecular weight was found to be induced. This protein was identified as a haemoprotein and had an electrophoretic mobility different from the proteins preferentially induced by either phenobarbitone or 20-methylcholanthrene treatment. Both the isosafrole-induced protein and the isosafrole metabolite-cytochrome P-450 complex were observed in microsomal preparations from rats which had received phenobarbitone and isosafrole or 20-methylcholanthrene and isosafrole, Isosafrole-related material was also found to be apparently irreversibly bound to rat and mouse proteins following the administration of [o-[14]C] isosafrole in vivo

Development and application of a PBPK modeling strategy to support antimalarial drug development

Abstract As part of a collaboration between Medicines for Malaria Venture (MMV), Certara UK and Monash University, physiologically‐based pharmacokinetic (PBPK) models were developed for 20 antimalarials, using data obtained from standardized in vitro assays and clinical studies within the literature. The models have been applied within antimalarial drug development at MMV for more than 5 years. During this time, a strategy for their impactful use has evolved. All models are described in the supplementary material and are available to researchers. Case studies are also presented, demonstrating real‐world development and clinical applications, including the assessment of the drug–drug interaction liability between combination partners or with co‐administered drugs. This work emphasizes the benefit of PBPK modeling for antimalarial drug development and decision making, and presents a strategy to integrate it into the research and development process. It also provides a repository of shared information to benefit the global health research community