Use of Freund's Complete Adjuvant (FCA) in inflammatory pain models: consequences on the metabolism and pharmacokinetics of the non-peptidic delta receptor agonist SNC80 in the rat.
This study was initiated to characterize the metabolism and pharmacokinetics of SNC80 in rats and to evaluate the impact of Freund's complete adjuvant (FCA)-induced inflammation on its body disposition. In vitro, the disappearance and intrinsic clearance (CL(int)) of SNC80 were measured following incubations in recombinant rat CYPs and in phenotyped liver microsomes from naive and 24-h FCA-treated rats. The unbound fraction (f(u)) was assessed by ultrafiltration. Based on the Clint values, in vivo blood clearance of 3.35 and 2.48 L/h/kg were predicted in naive and FCA-treated rats. In vivo, SNC80 was administered to naive and 24-h FCA-treated rats at 10 micromol/kg i.v. and 50 micromol/kg p.o. The naive animals showed high plasma clearance (3.1 L/h/kg), low renal clearance (<0.02 L/h/kg) and poor bioavailability (<4%). Following i.v. administration, plasma clearance was lower (22%) in FCA-treated vs. untreated rats. Despite the decreases in f(u) (approximately 30%) and CL(int) (approximately 40%) in vitro, in vivo the apparent bioavailability and oral clearance were not significantly different between FCA-treated and naive rats. Hepatic and possibly intestinal losses contribute to the low bioavailability of SNC80. Non-hepatic mechanisms may compensate for the decrease in plasma clearance found in FCA-treated rats, preventing an increase in the oral bioavailability of SNC80.
Projean
D
D
Université de Montréal, Canada. denis.projean@astrazeneca.com
Lessard
E
E
Ducharme
M P
MP
Ducharme
J
J
D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D001682:Biological Availability; D001798:Blood Proteins; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000494:pharmacology*; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009961:Orosomucoid; D010146:Pain / Q000473:pathology*; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D011994:Recombinant Proteins / Q000378:metabolism; D012996:Solutions
D001549:Benzamides; D001798:Blood Proteins; D006023:Glycoproteins; C506108:Orm1 protein, rat; D009961:Orosomucoid; D010879:Piperazines; D017465:Receptors, Opioid, delta; D011994:Recombinant Proteins; D012996:Solutions; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D005620:Freund's Adjuvant; D003577:Cytochrome P-450 Enzyme System