title: Formation and pharmacokinetics of the active drug candoxatrilat in mouse, rat, rabbit, dog and man following administration of the prodrug candoxatril.
abstract: 1. Candoxatrilat, an active neutral endopeptidase inhibitor, was released rapidly from the inactive prodrug candoxatril in vivo in mouse, rat, rabbit, dog and man. 2. Oral doses of [14C]-candoxatril were cleared rapidly, mostly by ester hydrolysis to candoxatrilat, in mouse, dog and man. A complementary intravenous study in man with [14C]-candoxatrilat showed that the active drug was virtually completely renally cleared. Neither candoxatril nor candoxatrilat underwent chiral inversion in man. 3. Systemic availability of candoxatrilat from the oral prodrug was estimated to be 88, 53, 42, 17 and 32% in mouse, rat, rabbit, dog and man respectively. Plasma clearance of candoxatril was too rapid to enable pharmacokinetic parameter calculation in mouse and rabbit; for man, the apparent oral clearance was 57.9 ml/min/kg and the elimination half-life was 0.46 h. 4. For intravenous candoxatrilat, total plasma clearance values were 32, 15, 5.5, 5.8 and 1.9 ml/min/kg for mouse, rat, rabbit, dog and man respectively. Renal clearance values were 8.7, 7.2, 2.9 and 1.7 ml/min/kg for mouse, rat, dog and man and these approximate to the respective glomerular filtration rates. Allometric scaling with respect to bodyweight across the species allowed reasonable prediction of the above two clearance parameters in man.
authors.affiliation: Department of Drug Metabolism, Pfizer Central Research, Sandwich, UK.
authors.forename: B
authors.initials: B
authors.lastname: Kaye
authors.forename: C J
authors.initials: CJ
authors.lastname: Brearley
authors.forename: N J
authors.initials: NJ
authors.lastname: Cussans
authors.forename: M
authors.initials: M
authors.lastname: Herron
authors.forename: M J
authors.initials: MJ
authors.lastname: Humphrey
authors.forename: A R
authors.initials: AR
authors.lastname: Mollatt
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000328:Adult; D000818:Animals; D002250:Carbon Radioisotopes; D003509:Cyclohexanecarboxylic Acids / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004285:Dogs; D005243:Feces / Q000737:chemistry; D006801:Humans; D007189:Indans / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008875:Middle Aged; D011355:Prodrugs / Q000493:pharmacokinetics*; D011422:Propionates / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011480:Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D002250:Carbon Radioisotopes; D003509:Cyclohexanecarboxylic Acids; D007189:Indans; D011355:Prodrugs; D011422:Propionates; D011480:Protease Inhibitors; C060942:candoxatrilat; C062766:candoxatril