Hepatic biotransformation of the new calcium-mimetic agent, RWJ-68025, in the rat and in man--API-MS/MS identification of metabolites.
The in-vitro biotransformation of a new calcium-mimetic agent and benzenemethanamine analogue, RWJ-68025, was studied after incubation with rat and human hepatic S9 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.
Wu
Wu-Nan
WN
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, PA, USA. wwu@prdus.jnj.com
McKown
Linda A
LA
Rybczynski
Philip J
PJ
Demarest
Keith
K
D000818:Animals; D001711:Biotransformation; D002118:Calcium / Q000819:agonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D003521:Cyclopropanes / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D018716:Molecular Mimicry; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
C476290:1-R-phenyl-2-R-(1-(3-methoxyphenyl)-R-ethylamino)methylcyclopropane; D003521:Cyclopropanes; D002118:Calcium