Dong, Y. and Sonawane, Y. and Maher, S. P. and Zeeman, A. M. and Chaumeau, V. and Vantaux, A. and Cooper, C. A. and Chiu, F. C. K. and Ryan, E. and McLaren, J. and Chen, G. and Wittlin, S. and Witkowski, B. and Nosten, F. and Sriraghavan, K. and Kyle, D. E. and Kocken, C. H. M. and Charman, S. A. and Vennerstrom, J. L.. (2022) Metabolic, pharmacokinetic, and activity profile of the liver stage antimalarial (RC-12). ACS Omega, 7 (14). pp. 12401-12411.
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Official URL: https://edoc.unibas.ch/90446/
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Abstract
The catechol derivative RC-12 (WR 27653) (1) is one of the few non-8-aminoquinolines with good activity against hypnozoites in the gold-standard Plasmodium cynomolgi-rhesus monkey (Macaca mulatta) model, but in a small clinical trial, it had no efficacy against Plasmodium vivax hypnozoites. In an attempt to better understand the pharmacokinetic and pharmacodynamic profile of 1 and to identify potential active metabolites, we now describe the phase I metabolism, rat pharmacokinetics, and in vitro liver-stage activity of 1 and its metabolites. Compound 1 had a distinct metabolic profile in human vs monkey liver microsomes, and the data suggested that the O-desmethyl, combined O-desmethyl/N-desethyl, and N,N-didesethyl metabolites (or a combination thereof) could potentially account for the superior liver stage antimalarial efficacy of 1 in rhesus monkeys vs that seen in humans. Indeed, the rate of metabolism was considerably lower in human liver microsomes in comparison to rhesus monkey microsomes, as was the formation of the combined O-desmethyl/N-desethyl metabolite, which was the only metabolite tested that had any activity against liver-stage P. vivax; however, it was not consistently active against liver-stage P. cynomolgi. As 1 and all but one of its identified Phase I metabolites had no in vitro activity against P. vivax or P. cynomolgi liver-stage malaria parasites, we suggest that there may be additional unidentified active metabolites of 1 or that the exposure of 1 achieved in the reported unsuccessful clinical trial of this drug candidate was insufficient to kill the P. vivax hypnozoites.
Faculties and Departments: | 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser) |
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UniBasel Contributors: | Wittlin, Sergio |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
ISSN: | 2470-1343 (Electronic)2470-1343 (Linking) |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Identification Number: |
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Last Modified: | 21 Dec 2022 18:34 |
Deposited On: | 21 Dec 2022 18:34 |
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