Hepatic biotransformation of the new calcium-mimetic agent, RWJ-68025, in the rat and in man - API-MS/MS identification of metabolites

• Published in: Journal of pharmacy and pharmacology Vol. 55; no. 5; pp. 631 - 637
• Main Authors: Wu, WN, McKown, LA, Rybczynski, PJ, Demarest, K
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.05.2003
• Subjects: Animals; Biotransformation; Calcium - agonists; Calcium - chemistry; Calcium - metabolism; Calcium - pharmacology; Cyclopropanes - analysis; Cyclopropanes - chemistry; Cyclopropanes - metabolism; Humans; Life Sciences & Biomedicine; Liver - metabolism; Male; Molecular Mimicry; Pharmacology & Pharmacy; Rats; Science & Technology; Spectrometry, Mass, Electrospray Ionization - methods; EXTRACELLULAR CA2+-SENSING RECEPTOR; NPS R-568; CALCIMIMETIC COMPOUND
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1211/002235703765344531

The in-vitro biotransformation of a new calcium-mimetic agent and benzenemethanamine analogue, RWJ-68025, was studied after incubation with rat and human hepatic 59 fractions in the presence of an NADPH-generating system. Unchanged RWJ-68025 (44-48% of the sample) plus 12 metabolites were profiled, quantified, and tentatively identified on the basis of API (ionspray)MS and MS/MS data, and ethyl derivatization for phenolic and carboxylic metabolites. Four metabolic pathways for RWJ-68025 were proposed: pathway 1, O-demethylation; pathway 2, phenyl oxidation; pathway 3, methyl oxidation; and pathway 4, N-dealkylation/acetylation. Pathway 1 formed a major metabolite, O-desmethyl-RWJ-68025 (M1; RWJ-68311; 26% in rat; 16% in human fraction). Pathway 2 produced one major (M2; 12-17% in rat and human fraction) and two minor phenolic metabolites (M4 and M5; all <1% in both species), and in conjunction with step 1, formed hydroxy-M1 (M3; 4-5% in both species). Pathways 3 and 4 formed seven minor oxidized metabolites (M6-M12). RWJ-68025 was extensively metabolized in the rat and human hepatic S9 fractions.