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M Hirobe

Publications and source records attributed to M Hirobe.

131 records · Page 8Linked to original sources
PubMedDate not supplied

Metabolism and penetration through blood-brain barrier of parkinsonism-related compounds. 1,2,3,4-Tetrahydroisoquinoline and 1-methyl-1,2,3,4-tetrahydroisoquinoline.

14C-Labeled 1,2,3,4-tetrahydroisoquinoline (TIQ) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) were synthesized, and their metabolism and tissue distribution were studied. Both compounds showed similar metabolic patterns. In 24 hr after po administration (50 mg/kg) to rats, 76% of TIQ and 72% of 1MeTIQ were excreted unchanged, and 2.7 and 8.7% were excreted as the 4-hydroxyl derivatives, 4-hydroxy-TIQ and 4-hydroxy-1MeTIQ, respectively. Small amounts of N-methylated metabolites, 2-methyl-TIQ (0.4%) and 2-methyl-1MeTIQ (0.7%) were detected. Isoquinoline (2.5%) also was found as a metabolite of TIQ and 1-methyl-3,4-dihydroisoquinoline (1.0%) was found as a metabolite of 1MeTIQ. The concentration of labeled compounds in the brain was about 4.5-fold higher than the blood concentration at 4 hr after dosing, and over 90% was unchanged TIQ or 1MeTIQ. These data indicated that TIQ and 1MeTIQ easily passed through the blood-brain barrier and were concentrated in the brain. Thus, it appears that TIQ and 1MeTIQ as endogenous or exogenous amines may accumulate in the brain and may be related to the onset of Parkinson's disease.

Animals↗
PubMedDate not supplied

Application of chemical cytochrome P-450 model systems to studies on drug metabolism. IV. Mechanism of piperidine metabolism pathways via an iminium intermediate.

Oxidations of the piperidine ring by chemical model and liver microsomal systems were investigated with a simple piperidine derivative, N-benzylpiperidine (BP) (3), as the substrate in order to probe the generality and the mechanism of the biotransformation of the piperidine ring. The piperidine ring of BP (3) as well as that of phencyclidine (1) was suggested to be oxidized to a ketone at the beta-position in the meso-tetraphenylporphinatoiron(III) chloride system, and the reaction was expected to occur in the liver microsomal system. The beta-oxo formation was observed directly in the liver microsomal system, and found to be dependent on cytochrome P-450. Then it was suggested that the piperidine-beta-oxo formation was a general oxidation pathway of the piperidine biotransformation. Hydrogen abstraction in the reaction was not a rate-determining step. Therefore, we presumed a possible mechanism of beta-oxo formation via BP-iminium (21). From the comparative study on the reactivities of dipropylbenzylamine (DPB) (18) and BP (3), and the stabilities of iminium (Im+) species of BP (3) and DPB (18), it was suggested that BP-Im+ (21) was relatively stable and was the most likely precursor of BP-beta-oxo (6). BP-Im+ (21) and its free base, enamine (29), afforded large amounts of BP-beta-oxo as well as BP-alpha-oxo (9) in the chemical model and the microsomal systems. This evidence supported the iminium-enamine mechanism expressed as scheme III.

Animals↗
PubMedDate not supplied

Studies on the metabolism of tulobuterol . HCl. Identification of basic urinary metabolites in the dog, rat, rabbit, and guinea pig.

The metabolism of tulobuterol, a new bronchodilating agent, has been studied in the dog, rat, rabbit, and guinea pig. Major basic metabolites of tulobuterol excreted in the urine were identified by comparison of the retention times of a gas chromatogram and/or a mass chromatogram, and of mass spectra with those of the authentic compounds. 4,5-Dihydroxytulobuterol and/or 4-hydroxy-3-methoxytulobuterol were identified in the urine of these species. There were species differences in the extent and direction of ring-hydroxylation and subsequent O-methylation.

Animals↗
PubMedDate not supplied

Inter-individual differences of 4-[4-(4-methylphenyl)-phenylmethoxy-1-piperidinyl]butyric acid disposition in rats: possible involvement of genetic polymorphism.

Inter-individual differences of drug plasma concentration were recognized in outbred rats after an oral or intravenous administration of (+)-4-[4-(4-methylphenyl)phenylmethoxy-1-piperidinyl]butyric acid hydrochloride ((+)-MPPB). Rats could be divided into two phenotypes, the rapid metabolizing (RM) group and the slow metabolizing (SM) group. The hepatic clearance of RM-phenotyped Sprague-Dawley rats was about 10 times larger than that of the SM group. Outbred male and female Sprague-Dawley rats and male Wistar rats were mixtures of the RM and SM groups. On the other hand, all inbred male Lewis rats were RM, and all inbred male F344 and ACI rats were SM. This study was undertaken to investigate the inter-individual differences of (-)-MPPB and the metabolic pathways of (+)- and (-)-MPPB. When (-)-MPPB was orally administered to male Sprague-Dawley rats, similar inter-individual differences of plasma concentration were recognized. RM-phenotyped Sprague-Dawley rat liver microsomes metabolized (+)-MPPB to 4-hydroxymethylphenyl-MPPB (M1), and (-)-MPPB to M1 and 4'-hydroxyphenyl-MPPB (M2). The formation of these metabolites was less with SM-phenotyped than with RM-phenotyped Sprague-Dawley rat liver microsomes. The kinetic parameters of M1 formation from (+)-MPPB by RM-phenotyped rat liver microsomes were characteristic of a two-enzyme system with a 100-fold difference in their affinities (KM values). On the other hand, SM-phenotyped rats have only the low-affinity enzyme system. An inhibition study demonstrated that both enzymes were cytochrome P450.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗