Metabolic, Pharmacokinetic, and Activity Profile of the Liver Stage Antimalarial (RC-12)
Issued Date
2022-04-12
Resource Type
eISSN
24701343
Scopus ID
2-s2.0-85127988288
Journal Title
ACS Omega
Volume
7
Issue
14
Start Page
12401
End Page
12411
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Omega Vol.7 No.14 (2022) , 12401-12411
Suggested Citation
Dong Y., Sonawane Y., Maher S.P., Zeeman A.M., Chaumeau V., Vantaux A., Cooper C.A., Chiu F.C.K., Ryan E., McLaren J., Chen G., Wittlin S., Witkowski B., Nosten F., Sriraghavan K., Kyle D.E., Kocken C.H.M., Charman S.A., Vennerstrom J.L. Metabolic, Pharmacokinetic, and Activity Profile of the Liver Stage Antimalarial (RC-12). ACS Omega Vol.7 No.14 (2022) , 12401-12411. 12411. doi:10.1021/acsomega.2c01099 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/84093
Title
Metabolic, Pharmacokinetic, and Activity Profile of the Liver Stage Antimalarial (RC-12)
Author's Affiliation
Faculty of Tropical Medicine, Mahidol University
Monash University, Centre for Drug Candidate Optimisation
Institut Pasteur du Cambodge
University of Georgia
College of Pharmacy
Swiss Tropical and Public Health Institute (Swiss TPH)
Biomedical Primate Research Centre - Rijswijk
Nuffield Department of Medicine
Monash University, Centre for Drug Candidate Optimisation
Institut Pasteur du Cambodge
University of Georgia
College of Pharmacy
Swiss Tropical and Public Health Institute (Swiss TPH)
Biomedical Primate Research Centre - Rijswijk
Nuffield Department of Medicine
Other Contributor(s)
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.