title: Pharmacokinetics, disposition and lipid-modulating activity of 5-{2-[4-(3,4-difluorophenoxy)-phenyl]-ethylsulfamoyl}-2-methyl-benzoic acid, a potent and subtype-selective peroxisome proliferator-activated receptor alpha agonist in preclinical species and human.
abstract: 5-{2-[4-(3,4-Difluorophenoxy)-phenyl]-ethylsulfamoyl}-2-methyl-benzoic acid (1) is a novel, potent, and selective agonist of the peroxisome proliferator-activated receptor alpha (PPAR-alpha). In preclinical species, compound 1 demonstrated generally favourable pharmacokinetic properties. Systemic plasma clearance (CLp) after intravenous administration was low in Sprague-Dawley rats (3.2 +/- 1.4 ml min(-1) kg(-1)) and cynomolgus monkeys (6.1 +/- 1.6 ml min(-1) kg(-1)) resulting in plasma half-lives of 7.1 +/- 0.7 h and 9.4 +/- 0.8 h, respectively. Moderate bioavailability in rats (64%) and monkeys (55%) was observed after oral dosing. In rats, oral pharmacokinetics were dose-dependent over the dose range examined (10 and 50 mg kg(-1)). In vitro metabolism studies on 1 in cryopreserved rat, monkey, and human hepatocytes revealed that 1 was metabolized via oxidation and phase II glucuronidation pathways. In rats, a percentage of the dose (approximately 19%) was eliminated via biliary excretion in the unchanged form. Studies using recombinant human CYP isozymes established that the rate-limiting step in the oxidative metabolism of 1 to the major primary alcohol metabolite M1 was catalysed by CYP3A4. Compound 1 was greater than 99% bound to plasma proteins in rat, monkey, mouse, and human. No competitive inhibition of the five major cytochrome P450 enzymes, namely CYP1A2, P4502C9, P4502C19, P4502D6 and P4503A4 (IC50's > 30 microM) was discerned with 1. Because of insignificant turnover of 1 in human liver microsomes and hepatocytes, human clearance was predicted using rat single-species allometric scaling from in vivo data. The steady-state volume was also scaled from rat volume after normalization for protein-binding differences. As such, these estimates were used to predict an efficacious human dose required for 30% lowering of triglycerides. In order to aid human dose projections, pharmacokinetic/pharmacodynamic relationships for triglyceride lowering by 1 were first established in mice, which allowed an insight into the efficacious concentrations required for maximal triglyceride lowering. Assuming that the pharmacology translated in a quantitative fashion from mouse to human, dose projections were made for humans using mouse pharmacodynamic parameters and the predicted human pharmacokinetic estimates. First-in-human clinical studies on 1 following oral administration suggested that the human pharmacokinetics/dose predictions were in the range that yielded a favourable pharmacodynamic response.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, CT 06340, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Frederick
authors.forename: T S
authors.initials: TS
authors.lastname: Maurer
authors.forename: A S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: L J
authors.initials: LJ
authors.lastname: Royer
authors.forename: O L
authors.initials: OL
authors.lastname: Francone
authors.forename: S M
authors.initials: SM
authors.lastname: Winter
authors.forename: S G
authors.initials: SG
authors.lastname: Terra
authors.forename: D
authors.initials: D
authors.lastname: Chen
authors.forename: X
authors.initials: X
authors.lastname: Gao
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D047493:PPAR alpha / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000037:antagonists & inhibitors / Q000097:blood
chemical_list: C546071:5-(2-(4-(3,4-difluorophenoxy)phenyl)ethylsulfamoyl)-2-methyl-benzoic acid; D001565:Benzoates; D065607:Cytochrome P-450 Enzyme Inhibitors; D047493:PPAR alpha; D014280:Triglycerides; D003577:Cytochrome P-450 Enzyme System