Pharmacokinetics and metabolism of NO-1886, a lipoprotein lipase-promoting agent, in cynomolgus monkey

Abstract

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.

Assessment of Induction of Cytochrome P450 by NO-1886 (Ibrolipim), a Lipoprotein Lipase-Promoting Agent, in Primary Cultures of Human Hepatocytes and in Female Rat Liver

“…After repeated oral administration of NO-1886 at a dose of 30 mg W kg once a day for 14 days, the Cmax value was 15.1 mg W mL. Taking into consideration the protein binding ratio in rat serum (93.2z), 6) the free plasma concentration of NO-1886 was about 2.3 mM. At this concentration, the levels of CYP mRNA were not changed, in agreement with the protein levels of CYP isoforms.…”

“…The free plasma concentration of NO-1886 in humans was estimated to be 0.23 mM at a dose of 3 mg W kg, based on 93.3z protein binding of NO-1886 in human serum. 6) The fact that 2 mM of NO-1886 in the culture medium did not aŠect the mRNA expression levels of CYP isoforms suggests that the expression levels of CYP2Cs and CYP3As should not be aŠected by the administration of NO-1886 in the clinical setting. However, the intended targets of NO-1886 in clinical use are the chemoprevention of diseases such as colon cancer 3) and atherosclerosis, 1) which would require longterm drug therapy and may also involve the co-administration of other drugs.…”

“…Plasma NO-1886 concentrations were determined by high-performance liquid chromatography (HPLC). 6) From the plasma concentration proˆle, the maximum plasma concentration (Cmax) and the time point of the maximum plasma concentration (Tmax) were obtained. The elimination half-life (T 1 W 2 ) was estimated as ln 2 W k, where k is the slope of the terminal linear portion of the logarithmic plasma concentration-time curve.…”

“…Morioka et al [4][5][6] have previously reported the pharmacokinetics and metabolic pathways ( Fig. 1) of NO-1886.…”

“…The in vivo metabolic pathways of NO-1886 in the rat and the cynomolgus monkey have been identiˆed as the O-deethylation of phosphonate and the hydrolysis of the amide bond. 4,6) The main metabolite is monoethyl phosphonate (M-2), which has been reported to account for 70z and 94z of all metabolites in the rat 4) and the cynomolgus monkey, 6) respectively. It has been demonstrated that the O-deethylation of phosphonate is performed by liver CYP isoforms and that the amino bond is hydrolyzed by liver microsomal carboxylesterase (CES).…”