The pharmacokinetics and metabolism of CP-191,166, an angiotensin II receptor antagonist, in rats and dogs.
CP-191,166 is an orally active, non-peptide angiotensin II (AII) receptor antagonist developed for the treatment of hypertension and congestive heart failure (CHF). In this study, the intravenous (iv) and oral (po) single dose pharmacokinetics (PK), oral multiple dose PK and P450-mediated metabolism of CP-191,166 were determined in rats and dogs. CP-191,166 was administered in both single and multiple (22-29 day) doses to Sprague-Dawley rats (3 mg/kg iv and 5, 10, 25 and 200 mg/kg po) and to beagle dogs (5 mg/kg iv and 5, 15 and 50 mg/kg po). Blood samples were collected between 0 and 48 h and plasma CP-191,166 concentrations were determined using high performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The in vitro metabolism of CP-191,166 was also evaluated with rat and dog liver microsomes. The results of these studies suggest that in both species, there may be saturable clearance occurring with higher doses, T(max) was at or near the earliest sample time point for all doses, suggesting that the drug was rapidly absorbed, and CP-191,166 was eliminated with t(1/2) values of 8-9 h. No rat or dog microsomal metabolism was observed, suggesting that metabolites detected in vivo in dogs were non-P450-mediated.
Allen
M C
MC
Drug Metabolism Development Department, Pfizer Central Research, Groton, CT 06340, USA.
Nocerini
M R
MR
Day
W W
WW
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006207:Half-Life; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; C099503:CP 191166; D007093:Imidazoles; D011725:Pyridines; D000804:Angiotensin II