title: Pharmacokinetics and elucidation of the rates and routes of N-glucuronidation of PF-592379, an oral dopamine 3 agonist in rat, dog, and human.
abstract: PF-592379 is a potent, selective agonist of the dopamine 3 receptor, for the treatment of male erectile dysfunction and female sexual dysfunction. In vivo, PF-592379 has low-moderate clearance relative to liver blood flow of 6.3 and 8.5 ml/min/kg in dog and 44.8 and 58.2 ml/min/kg in rat. It has high permeability in Caco-2 cells and was completely absorbed in rat and dog pharmacokinetic studies with an oral bioavailability of 28% in both rats and 61 and 87% in the dogs. These data are consistent with the physicochemical properties of PF-592379, which indicate complete absorption by the transcellular route. Elimination of PF-592379 was predominantly metabolic in nature. In vitro routes of metabolism studies indicate that metabolism in the rat is a combination of P450 mechanisms and N-glucuronidation, whereas in dog and human, N-glucuronidation is the major route. NMR analysis indicates that N-glucuronidation is non-quaternary in nature and occurs on both the pyridyl amine and ring nitrogen. Rates of clearance via N-glucuronidation were predicted to be low in humans compared with acyl or phenolic glucuronidation. PF-592379 was predicted to have complete absorption from the gastrointestinal tract and an oral bioavailability of >60% in the clinic. Clinical data verified that PF-592379 is a low clearance compound in human, with a mean oral clearance of 6.5 ml/min/kg following a 200 mg oral dose. PF-592379 has ideal pharmacokinetic properties for an oral D3 agonist, intended for on demand dosing.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, UK. Neil.attkins@pfizer.com
authors.forename: Neil
authors.initials: N
authors.lastname: Attkins
authors.forename: Alison
authors.initials: A
authors.lastname: Betts
authors.forename: David
authors.initials: D
authors.lastname: Hepworth
authors.forename: Anne C
authors.initials: AC
authors.lastname: Heatherington
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001699:Biometry; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D004285:Dogs; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004353:Drug Evaluation, Preclinical; D007172:Erectile Dysfunction / Q000188:drug therapy; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D009025:Morpholines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists*
chemical_list: D000631:Aminopyridines; D001798:Blood Proteins; D018491:Dopamine Agonists; D009025:Morpholines; C555358:PF 592379; D050637:Receptors, Dopamine D3; D014453:Glucuronosyltransferase