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J Dow

Publications and source records attributed to J Dow.

78 records · Page 5Linked to original sources
PubMedDate not supplied

Cardioselectivity of alpha-tocopherol analogues, with free radical scavenger activity, in the rat.

MDL74270 (6-acetyloxy-3,4-dihydro-N,N,N,2,5,7, 8-heptamethyl-2H-1-benzopyran-2-ethanaminium, 4-methylbenzenesulfonate) is a quaternary amine analogue of alpha-tocopherol with free radical scavenger properties. Rats were injected iv with [14C]MDL74270 (0.91 mg/kg), and whole blood and heart tissue were sampled. Five min after drug, the heart tissue/blood ratio (T/B) of radioactivity was 3.5, whereas at 1 hr it was 20.1 and remained at this value up to at least 6 hr. After iv administration the t 1/2 of radioactivity in blood was 6.3 hr, but po blood levels could not be quantified. The 0- to 96-hr urinary elimination of radioactivity was 39.9 +/- 5.7% of the dose after iv and only 1.2 +/- 0.4% after po administration, conversely, 44.7 +/- 5.2% was excreted in feces after iv and 79.1 +/- 17.4% after po administration. These results confirmed poor oral absorption of the compound. Tissue distribution of [14C]MDL74270 was compared with that of its tertiary amine analogue [14C]MDL74366 in rat heart, skeletal muscle, brain, and whole blood, after iv administration (1 mg/kg). The heart T/B was above 20, 1-6 hr after [14C]MDL74270, whereas it was less than 2 after [14C]MDL74366. Over the 1- to 6-hr time interval, skeletal muscle T/B varied from 1.8 to 5 compared with 1.5 to 0.6 for [14C] MDL74366. Brain T/B was higher after the tertiary amine compound. Results showed marked cardioselectivity of radioactivity after [14C] MDL74270. Differential centrifugation of heart homogenates showed that radioactivity was equally distributed between the major subcellular fractions studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Localization of a new benzamide derivative, tropapride and of 1-sulpiride, in the pituitary gland of the rat.

Localization of tropapride and 1-sulpiride in the pituitary gland of the rat has been studied. A comparison of the ratio of total radioactivity in pituitary/total radioactivity in blood after i.p. administration shows that 1-sulpiride has a greater and more persistent localization in the pituitary than tropapride. Tropapride is present in this gland at 0.16 microM concentration 1 hour after an oral dose of 0.4 mg/kg, which is the ED50 value in a test related to neuroleptic activity: the antagonism of apomorphine-induced stereotypies. 1-Sulpiride, administered orally at doses near the ED50 value in the same test, gives after 1 hour pituitary concentrations at least thousand times greater.

Administration, Oral↗
PubMedDate not supplied

Novel carbamate metabolites of mofegiline, a primary amine monoamine oxidase B inhibitor, in dogs and humans.

Mofegiline or MDL 72,974A ((E)-4-fluoro-beta-fluoromethylene benzene butanamine hydrochloride) is a selective enzyme-activated irreversible inhibitor of monoamine oxidase B, which is under development for use in the treatment of Parkinson's disease. Male beagle dogs were given single p.o. (20 mg/kg) and i.v. (5 mg/kg) doses of [14C]-Mofegiline. Total radioactivity excreted in urine and feces over 96 hr was, respectively, 75.5 +/- 3.8 and 6.3 +/- 3.4% of the dose after p.o. and 67.9 +/- 0.5 and 3.9 +/- 2.4% after i.v. administration. Unchanged drug in urine represented 3% of the dose after po and less than 1% after i.v. administration. Mofegiline was thus extensively metabolized in dogs, and urinary excretion was the major route of elimination of metabolites. HPLC, with on-line radioactivity detection, showed the presence of four major peaks (M1, M2, M3, and M4), representing respectively 50, 9, 5, and 0.5% of the administered dose excreted in 0-24 hr urine. TSP-LC-MS, FAB-MS, and NMR spectra of the purified metabolites were obtained. M1, the major metabolite in dogs, was shown to have undergone defluorination of the beta-fluoromethylene moiety, and one carbon addition. Its structure was confirmed to be a cyclic carbamate. M2 was a N-carbamoyl O-beta-D-glucuronide conjugate of parent drug. The formation of M1 and M2 is likely to involve initial reversible addition of CO2 to the primary amine function. M3 was a N-succinyl conjugate of the parent drug. M4 had also undergone defluorination to yield a urea adduct of an unsaturated alpha, beta aldehyde. Structures of M1 and M3 were further confirmed by comparing their MS and NMR spectra with those of authentic reference compounds. TSP-LC-MS ion chromatograms of human urine, obtained from two male volunteers after p.o. administration of 24 mg of drug, showed selected molecular ion peaks with the same retention time as the metabolites identified in dogs. In humans, these common metabolites represented a similar percentage of the administered dose to that in dogs. The present study demonstrates that NMR, TSP-LC-MS are complementary analytical techniques, which allow structural identification of unhydrolyzed drug conjugates. The formation of carbamates of amine-containing drugs may be more common than previously reported.

Administration, Oral↗