title: Preclinical drug metabolism and pharmacokinetic evaluation of GW844520, a novel anti-malarial mitochondrial electron transport inhibitor.
abstract: GW844520 is a potent and selective inhibitor of the cytochrome bc1 complex of mitochondrial electron transport in P. falciparum, the parasite primarily responsible for the mortality associated with malaria worldwide. GW844520 is fully active against the parasite including resistance isolates, showing no cross resistance with agents in use. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-malarial. GW844520 had low blood clearance of about 0.5-4% of hepatic blood flow and a steady-state volume of distribution of 2-4 times total body water in mouse, rat, dog, and monkey. Oral bioavailability was high (51-100%). Consistent with the in vivo data, GW844520 had low intrinsic clearance in liver microsomes and hepatocytes of animal and human origin, high passive cellular permeability and was not a P-glycoprotein substrate. GW844520 did not associate appreciably with blood cells but was highly bound to plasma proteins (>99%) in all species. GW844520 was a substrate and inhibitor of human CYP2D6 but not of CYP1A2, 2C9, 2C19, and 3A4. This conjunctive analysis supports continued evaluation of this compound in definitive pre-IND studies and exemplifies our strategy supporting the discovery of novel agents to treat diseases of the developing world.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Microbial, Musculoskeletal and Proliferative Diseases, Center of Excellence for Drug Discovery, GlaxoSmithKline R&D, 1250 South Collegeville Rd, Collegeville, PA 19426, USA. Hong.Xiang@gsk.com
authors.forename: Hong
authors.initials: H
authors.lastname: Xiang
authors.forename: Jeanelle
authors.initials: J
authors.lastname: McSurdy-Freed
authors.forename: Ganesh S
authors.initials: GS
authors.lastname: Moorthy
authors.forename: Erin
authors.initials: E
authors.lastname: Hugger
authors.forename: Ramesh
authors.initials: R
authors.lastname: Bambal
authors.forename: Chao
authors.initials: C
authors.lastname: Han
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.forename: Domingo
authors.initials: D
authors.lastname: Gargallo
authors.forename: Charles B
authors.initials: CB
authors.lastname: Davis
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics*; D001692:Biological Transport; D001711:Biotransformation; D002460:Cell Line; D002463:Cell Membrane Permeability; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D011728:Pyridones / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000962:Antimalarials; D065607:Cytochrome P-450 Enzyme Inhibitors; C517558:GW844520; D011728:Pyridones; D014450:Electron Transport Complex III