title: AFN-1252 in vitro absorption studies and pharmacokinetics following microdosing in healthy subjects.
abstract: OBJECTIVE
  To investigate the absorption, distribution, metabolism and excretion of AFN-1252, a novel inhibitor of the essential FabI enzyme in Staphylococcus spp., in vitro and following microdosing in healthy adult male subjects following intravenous and oral administration.
  
  
  METHODS
  Three ADME studies, comprising a Caco-2 assay, a rat intestinal perfusion model and a microdosing study in healthy human volunteers, were conducted.
  
  
  RESULTS
  The Caco-2 assay indicated that AFN-1252 in solution is well-absorbed and undergoes insignificant efflux, and its transport across the intestinal wall is probably passive. In the rat intestinal perfusion model, AFN-1252 exhibited high permeability potential across three segments, in the rank order of jejunum=ileum>colon. Taken together with the low aqueous solubility, the data from these studies indicate that AFN-1252 is a BCS Class II molecule with solubility-limited absorption. Analysis of the [(14)C]-AFN-1252 radioactivity concentration-time data indicated similar pharmacokinetics following intravenous and oral administration in the microdosing study in healthy volunteers. These included long terminal half-lives of ∼7 h and 83% bioavailability, indicating that there was little first-pass metabolism following oral dosing. AFN-1252 exhibited good distribution to skin and skin structures where its anti-staphylococcal activity may be required. Urinary and faecal excretion are major elimination routes for [(14)C]-AFN-1252 following intravenous or oral administration.
  
  
  CONCLUSIONS
  AFN-1252 has the potential for both intravenous and oral administration, once- or twice-daily dosing and good tissue distribution in humans. Further safety, efficacy and pharmacokinetic studies in man are required to investigate therapeutically-relevant doses for this novel agent and its targeted selectivity and high potency against Staphylococcus spp.
authors.affiliation: Affinium Pharmaceuticals, Inc., 200 Front Street West, Suite 3004, P.O. Box 31, Toronto, ON M5V 3K2, Canada. Electronic address: nkaplan@afnm.com.
authors.forename: Nachum
authors.initials: N
authors.lastname: Kaplan
authors.forename: Colin
authors.initials: C
authors.lastname: Garner
authors.forename: Barry
authors.initials: B
authors.lastname: Hafkin
mesh_terms: D000042:Absorption; D000293:Adolescent; D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D001572:Benzofurans / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D001768:Blister / Q000378:metabolism; D018938:Caco-2 Cells; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D011753:Pyrones / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: C521531:API 1252; D000900:Anti-Bacterial Agents; D001572:Benzofurans; D011753:Pyrones
keywords: ADME; AFN-1252; FabI inhibitor; Phase 0; Staphylococcus aureus