Hisao Tsukamoto

Biochemical basis for analgesic activity of morphine-6-glucuronide. I. Penetration of morphine-6-glucuronide in the brain of rats.

Abstract To understand the potent analgesic action of morphine-6-glucuronide (M-6-G), which was reported previously to be a minor metabolite of morphine in several mammalian species, the penetration of this conjugate into the brain was investigated using 14 C-labeled compound. A similar study was also conducted with 14 C-morphine. These studies presented evidence that, although M-6-G was a highly polar conjugate, it can penetrate the blood brain barrier and react with the receptor of analgesic action without prior hydrolysis of the glucuronide linkage. It was further suggested that the lack of analgesic activity produced with morphine-3-glucuronide (M-3-G), a major metabolite of morphine, was attributable to its inability to react with the receptor, because it penetrates the brain as well as M-6-G.

Eine verbesserte synthese von 2-acetamido-1-N-(4-L-aspartyl)-2-desoxy-β-D-glukopyranosylamin und die stereochemie seiner derivate

Abstract Crystalline 2-acetamido-2-deoxy-β- D -glucosylamine was prepared deacetylation of 2-acetamido-3,4,6-tri- O -acetyl-2-deoxy-β- D -glucopyranosyl azide followed by catalytic hydrogenation. An improved synthesis of 2-acetamido-1- N -(4- L -aspartyl)-2-deoxy-β- D -glucopyranosylamine is described. The configuration and conformation of its derivatives are discussed on the basis of the n.m.r. and o.r.d. spectra.

Metabolism of drugs—LVI: The metabolic fate of phenacetylurea

Abstract The identification of 4-hydroxyphenacetylurea and 3-methoxy-4-hydroxy-phenacetylurea in the urine of rabbits fed phenacetylurea is reported together with that of unchanged phenacetylurea. In addition to these metabolites, hydrolyzed metabolites, phenaceturic acid, and phenylacetic acid were also demonstrated to be excreted into the urine. However, unlike some drugs that possess an amide group in the molecule, the excretion of phenacetylurea N -glucuronide could not be recognized. It is considered from the above results that the metabolic fate of phenacetylurea consists of two different pathways: one is hydrolysis of the ureide group, and the other is successive hydroxylation and methylation of the benzene nucleus. The methyl acetyl derivative of phenacetylurea N -glucuronide was synthesized by acylation of methyl 1-deoxy-1-thioureido-2,3,4-tri-o-acetyl-β- d -glucopyranosiduronate with phenylacetylchloride, and subsequent desulfurization with silver nitrate. 4-Hydroxyphenacetylurea and 3-methoxy-4-hydroxyphenacetylurea were synthesized by condensation of the corresponding acid esters with urea.

Metabolism of drugs—LVII: Isolation, characterization and identification of p-nitrophenoxy acetic acid, a metabolite of butyl p-nitrophenyl ether in rats, mice and guinea pigs

Abstract The metabolism of butyl p-nitrophenyl ether in vivo in rats, mice, and guinea pigs was investigated and compared with that in rabbits. In the previous paper of this series, it was found that in rabbits this substance was metabolized mainly to (+)-3-hydroxybutyl p-nitrophenyl ether through the penultimate hydroxylation on its butyl chain, although the O-dealkylation reaction, the common metabolic pathway of alkylaryl ethers, occurred to a lesser extent. It was shown in the present study that, in addition to the two metabolites described above, rats and mice excreted a considerable amount of a new metabolite, p-nitrophenoxy acetic acid, which was produced probably by sucessive ω- and β-oxidation on the butyl group. Rabbits and guinea pigs, however, showed a remarkable species difference in the metabolism, excreting only a little of such carboxylic acid.

Metabolism of butyl p-nitrophenyl ether in vitro with rabbit liver preparations.

1. The metabolism of butyl p-nitrophenyl ether in vitro has been investigated with rabbit liver preparations. 2. Evidence for three metabolic pathways is presented. These involve initial microsomal hydroxylation at alpha, omega--1 or the omega positions of the butyl chain. 3. (omega--1)-Hydroxybutyl p-nitrophenyl ether was oxidized chiefly by the soluble fraction to the corresponding (omega--1)-oxo derivative which spontaneously decomposed to give p-nitrophenol. 4. omega-Hydroxybutyl p-nitrophenyl ether identified as a metabolite was further oxidized by the soluble fraction to p-nitrophenoxybutyric acid.

Metabolism of drugs—XLVIII. the study of selective demethylation of brucine in vivo

Abstract One of the two adjacent methoxyl groups attached to the aromatic ring of brucine was found to be demethylated selectively in rabbits. The predominant monophenolic metabolite was identified as 2-methoxy-3-hydroxystrychnine and excreted mostly as conjugated forms in the urine, mainly the β-glucuronide. The isomeric monophenol, 2-hydroxy-3-methoxystrychnine, was excreted in only a negligible amount. In addition to these phenolic metabolites, existence of a nonphenolic base in the urine was demonstrated, together with a very small amount of unchanged brucine, by paper chromatography. All of these metabolites and unchanged brucine were also excreted in feces, although the amounts were very small.

METABOLISM OF DRUGS. XLIX. THE STUDY OF SELECTIVE DEMETHYLATION OF 4-ACETAMINO- AND 4-NITRO-VERATROLES IN VIVO.

Abstract Both 4-acetamino- and 4-nitro-veratroles undergo an interesting selective demethylation as their major metabolic pathways in rabbits and produce 4-acetamino-and 4-nitro-guaiacols as the predominant metabolites, respectively. These findings, together with the preceding study on brucine, suggest that electronic configuration is not an important factor for occurrence of selective demethylation of two adjacent methoxyl groups attached to an aromatic ring system. No other reaction, including deacetylation or nitro reduction, has been demonstrated in either case except a slight formation of 4-nitrocatechol in the latter.

Metabolism of Drugs. XIX. Metabolic Fate of p-Aminosalicylic Acid in the Rabbit. (3).

The ether-type PAS-glucuronide was isolated as the acetyl-methyl derivative from the urine of rabbit receiving PAS and the structure was established as methyl (5-acet-amido-2-methoxycarbonylphenyl 2, 3, 4-tri-O-acetyl-β-D-glucopyranosid) uronate, which was chemically synthesized. The structure of m-aminophenyl glucuronide was identified with authentic specimen by means of infrared absorption spectra. It was confirmed by enzymatic hydrolysis that the glucuronides of PAS had the structure of β-D-glucopyranuronoside. The relation of m-aminophenol, m-aminophenyl sulfate, m-aminophenyl glucuronide, ether-type PAS-glucuronide, and PAS was discussed.