Pharmacokinetics and metabolism of NO-1886, a lipoprotein lipase-promoting agent, in cynomolgus monkey.
1. The study was conducted to investigate the pharmacokinetics and metabolism of NO-1886 (diethyl 4-[(4-bromo-2-cyanophenyl) carbamoyl] benzylphosphonate) in cynomolgus monkeys. 2. After single intravenous administration of NO-1886 at a dose of 3 mg kg(-1), the total clearance (CL(tot)), area under the plasma concentration-time curve (AUC(0-)(t)), half-life (t(1/2)), and volume of distribution (V(d)) in cynomolgus monkeys were 531 ml h(-1) kg(-1), 5.63 micro g h ml(-1), 0.96 h and 679 ml kg(-1), respectively. The AUC(0-)(t) for oral administration of NO-1886 (3 mg kg(-1)) was 4.23 micro g h ml(-1) and the bioavailability was 75%. 3. M-2 (ethyl 4-[(4-bromo-2-cyanophenyl) carbamoyl] benzylphosphonate) and M-3 (4-[(diethoxy-phosphoryl) methyl)] benzoic acid) were present as metabolites in plasma and urine. In faeces, M-2 was present but M-3 was not. 4. The major metabolite of NO-1886 in liver S9 or microsomes was M-2 in the presence of NADPH. On the other hand, M-3 was formed in the absence of NADPH in liver S9 or microsomes and its formation was inhibited by bis-( p-nitrophenyl) phosphate (BNPP) in liver S9, suggesting that the formation of M-3 was catalysed by carboxylesterase. 5. The findings suggest that the main metabolic pathway of NO-1886 in cynomolgus monkeys is the O-deethylation of NO-1886 to M-2, as in rats and humans, and that the hydrolysis of the amide bond is a minor metabolic pathway.
Morioka
Y
Y
Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc., Naruto, Tokushima, Japan. moriokyu@otsukakj.co.jp
Harada
M
M
Imai
T
T
Naito
S
S
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D005243:Feces; D006207:Half-Life; D007275:Injections, Intravenous; D008071:Lipoprotein Lipase / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000493:pharmacokinetics*
D001549:Benzamides; D001798:Blood Proteins; D009943:Organophosphorus Compounds; C082137:4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamide; D009249:NADP; D008071:Lipoprotein Lipase