Metabolism of diethyl 4-[(4-bromo-2-cyanophenyl)-carbamoyl]benzylphosphonate in the rat

Abstract

1. The metabolism of diethyl 4-[(4-bromo-2-cyanophenyl)carbamoyl]benzylphosphonate (NO-1886), an antilipidaemic agent, was evaluated in the rat. 2. 14C-NO-1886 was dosed orally to rats (3 mg/kg) and within 24 h after dosing, 27.9 +/- 2.1 and 63.5 +/- 4.2% of the administered radioactivity was recovered from urine and faeces respectively. 3. The metabolite M-2 was isolated from the urine and faeces, and two other metabolites, M-3 and M-5, were isolated from the urine. Two of them were identified as ethyl 4-[(4-bromo-2-cyanophenyl)carbamoyl]benzylphosphonate (M-2) and 4-[(diethoxy-phosphoryl)methyl)]benzoic acid (M-3), and the other one was considered to be 2-amino-5-bromo-3-cyanobenzene sulphate (M-5) by ms and nmr spectrometry. 4. The major metabolic pathway of NO-1886 was found to be mono-hydrolysis of the diethyl phosphonate. It was also considered that M-5 may have been formed in vivo via 2-amino-5-bromo-benzonitrile (M-1) and 2-amino-5-bromo-3-hydroxybenzonitrile (M-4).

PhosphonateO-Deethylation of [4-(4-Bromo-2-Cyano-Phenylcarbamoyl) Benzyl]-Phosphonic Acid Diethyl Ester, a Lipoprotein Lipase-Promoting Agent, Catalyzed by Cytochrome P450 2C8 and 3A4 in Human Liver Microsomes

“…The novel compound NO-1886 was shown to increase lipoprotein lipase activity and to induce an elevation of HDL cholesterol in a few studies (Tsutsumi et al, 1993(Tsutsumi et al, , 1995. The O-deethylation of the phosphoric acid ester of diethyl phosphonate and the hydrolysis of amide bonds have been reported to be the metabolic pathways of NO-1886, and the metabolites of NO-1886 do not increase lipoprotein lipase activity (Morioka et al, 1996). Because the disposition of NO-1886 has been investigated only in the rat (Morioka et al, 1996), it is necessary to clarify the metabolism of this new drug in humans.…”

“…The O-deethylation of the phosphoric acid ester of diethyl phosphonate and the hydrolysis of amide bonds have been reported to be the metabolic pathways of NO-1886, and the metabolites of NO-1886 do not increase lipoprotein lipase activity (Morioka et al, 1996). Because the disposition of NO-1886 has been investigated only in the rat (Morioka et al, 1996), it is necessary to clarify the metabolism of this new drug in humans. The enzymes involved in the metabolism of NO-1886 were therefore identified to obtain information to avoid drug-drug interactions in the clinical use of NO-1886.…”

“…As shown in Fig. 1, the metabolic pathways of NO-1886 in rats have been identified as 1) O-deethylation of the phosphoric acid ester, 2) hydrolysis of the amide bond, 3) hydroxylation of the amino compound (M-1) produced by hydrolysis of the amide bond, and 4) sulfation following hydroxylation of M-1 (Morioka et al, 1996). NO-1886 was almost completely excreted in the urine (28%) and feces (64%) as metabolites within 24 h of postdosing in rats that were maintained in metabolic cages.…”

“…NO-1886 was almost completely excreted in the urine (28%) and feces (64%) as metabolites within 24 h of postdosing in rats that were maintained in metabolic cages. The major metabolite was monoethyl phosphonate (M-2), which accounted for 70% of all metabolites in rats (Morioka et al, 1996). None of these metabolites, including the major metabolite (the monoester form), increases the activity of LPL (Morioka et al, 1996).…”

“…The major metabolite was monoethyl phosphonate (M-2), which accounted for 70% of all metabolites in rats (Morioka et al, 1996). None of these metabolites, including the major metabolite (the monoester form), increases the activity of LPL (Morioka et al, 1996). Therefore, the metabolic activity in humans is an important factor in determining the duration of administration in clinical use.…”