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 µg 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 µg 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.