Characterization of the Preclinical Pharmacology of the New 2-Aminomethylphenol, JPC-3210, for Malaria Treatment and Prevention
| Autor: | David P. Jacobus, Donna Mackenzie, Arba L. Ager, Gavin D. Heffernan, Pablo Rafael Morales, Karin van Breda, Laura R. Jacobus, John W. Anderson, G. Dennis Shanks, Guy A. Schiehser, Michael D. Edstein, Geoffrey W. Birrell, Marina Chavchich |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male 030106 microbiology Glucuronidation Pharmacology 03 medical and health sciences Antimalarials Mice Pharmacokinetics Cytochrome P-450 Enzyme System In vivo Animals Humans Pharmacology (medical) Cells Cultured biology CYP3A4 Chemistry Cytochrome P450 Plasmodium falciparum biology.organism_classification In vitro Drug Resistance Multiple Bioavailability Malaria Rats 030104 developmental biology Infectious Diseases biology.protein Hepatocytes Microsomes Liver Female Protein Binding |
| Popis: | The new 2-aminomethylphenol, JPC-3210, has potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity, and high in vivo efficacy against murine malaria. Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and the results of in vitro screening assays, including the inhibition of cytochrome P450 (CYP450) isozymes. In mice, JPC-3210 was rapidly absorbed and had an extensive tissue distribution, with a brain tissue-to-plasma concentration ratio of about 5.4. JPC-3210 had a lengthy plasma elimination half-life of about 4.5 days in mice and 11.8 days in monkeys. JPC-3210 exhibited linear single-oral-dose pharmacokinetics across the dose range of 5 to 40 mg/kg of body weight with high oral bioavailability (∼86%) in mice. Systemic blood exposure of JPC-3210 was 16.6% higher in P. berghei -infected mice than in healthy mice. In vitro studies with mice and human hepatocytes revealed little metabolism and the high metabolic stability of JPC-3210. The abundance of human metabolites from oxidation and glucuronidation was 2.0% and 2.5%, respectively. CYP450 studies in human liver microsomes showed JPC-3210 to be an inhibitor of CYP2D6 and, to a lesser extent, CYP3A4 isozymes, suggesting the possibility of a metabolic drug-drug interaction with drugs that are metabolized by these isozymes. In vitro studies showed that JPC-3210 is highly protein bound to human plasma (97%). These desirable pharmacological findings of a lengthy blood elimination half-life, high oral bioavailability, and low metabolism as well as high in vivo potency have led the Medicines for Malaria Venture to select JPC-3210 (MMV892646) for further advanced preclinical development. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|