The metabolic profile of azimilide in man: in vivo and in vitro evaluations.
The metabolic fate of azimilide in man is unusual as it undergoes a cleavage in vivo resulting in the formation of two classes of structurally distinct metabolites. During a metabolite profiling study conducted in human volunteers to assess the contribution of all pathways to the clearance of (14)C-azimilide, greater than 82% of radioactivity was recovered in urine (49%-58%) and feces (33%). Urine, feces, and plasma were profiled for metabolites. A cleaved metabolite, 4-chloro-2-phenyl furoic acid was present at high concentration in plasma (metabolite/parent AUC ratio approx. 4), while other plasma metabolites, azimilide N-oxide (metabolite/parent AUC ratio 0.001), and a cleaved hydantoin metabolite (metabolite/parent AUC ratio = 0.3) were present at lower concentrations than azimilide. In urine, the cleaved metabolites were the major metabolites, (> 35% of the dose) along with phenols (as conjugates, 7%-8%), azimilide N-oxide (4%-10%), a butanoic acid metabolite (2%-3%), and desmethyl azimilide (2%). A limited investigation of fecal metabolites indicated that azimilide (3%-5%), desmethyl azimilide (1%-3%), and the butanoic acid metabolite (< 1%) were present. Contributing pathways for metabolism of azimilide, identified through in vitro and in-vivo studies, were CYPs 1A1 (est. 28%), 3A4/5 (est. 20%), 2D6 (< 1%), FMO (est. 14%), and cleavage (35%). Enzyme(s) involved in the cleavage of azimilide were not identified.
Riley
P
P
Drug Safety Assessment, Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason Montgomery Road, Mason, Ohio.
Figary
P C
PC
Entwisle
J R
JR
Roe
A L
AL
Thompson
G A
GA
Ohashi
R
R
Ohashi
N
N
Moorehead
T J
TJ
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D002250:Carbon Radioisotopes; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D006801:Humans; D006827:Hydantoins; D048289:Imidazolidines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D002250:Carbon Radioisotopes; D006827:Hydantoins; D048289:Imidazolidines; D010879:Piperazines; C086123:azimilide; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019363:Cytochrome P-450 CYP1A1; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A