1992 Volume 7 Issue 6 Pages 853-869
The metabolism of (±)-3-(benzylmethylamino)-2, 2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylate hydrochrolide (TC-81) was studied in male rats and dogs after a single oral administration of 14C-TC-81 or d3-TC-81.
The fifteen metabolites of TC-81 were identified by gas-chromatography mass-spectrometric method and/or TLC and HPLC.
In rats urine, M-7 or M-12 were found as m ajor metabolites and their content was estimated to be about 1.0% of dose for 24hr after dosing. In rats bile, M-11 was found as a major metabolite and its content was estimated to be about 10.4% of dose for 48hr after dosing. In rat plasma, M-4 and M-6 were found as metabolites. M-4 was eliminated from plasma monophasically (t1/2 was from 1.0hr to 2.6hr), but M-6 was eliminated from plasma biphasically (t1/2(α) was from 2.7hr to 7.7hr and t1/2(β)was from 42.7hr to 58.0hr). In dogs urine, M-14 was found as a major metabolite and its content was estimated to be about 4.3% of dose for 24hr after dosing.
The proposed metabolic pathways of TC-81 were 1)oxidation of the dihydoropyridine moiety to the pyridine form, 2) metabolism the side chain at the 3-position, 3) hydrolysis the methyl ester at the 5-position, 4) hydroxylation of methyl group at 2- or 6-position, 5)conjugation and 6)defluorination.
