Pre-systemic metabolism of viprostol in the monkey following oral and topical administration.

1. 14C-Viprostol, (I), a synthetic PGE2 analogue, was administered to 6 monkeys, orally, topically and intravenously in a three way crossover study. Total radioactivity and the pharmacologically active acid formed by rapid hydrolysis of viprostol in vivo, (II), were measured in plasma to determine absorption and absolute bioavailability. 2. After oral dosing approx. 31% of drug-related radioactivity was absorbed. Systemic bioavailability of unchanged active acid was only 7.3%. This indicates significant first-pass metabolism after oral administration, since only 23% of the absorbed radioactivity was available as 'unchanged' active drug (II). 3. After topical dosing, transdermal absorption of total radioactivity by 48 h averaged only 5% of dose. Absolute bioavailability of II averaged 3.8% of dose. This indicates that after transdermal absorption 74% of the absorbed radioactivity was available systemically as the active acid II, with the remainder being subject to pre-systemic metabolism.

Identification of human urinary mitoxantrone metabolites.

Two polar metabolites of mitoxantrone, a clinically active antitumor agent, have been isolated and purified from the urine of patients by sequential absorption on glass wool and C18-Sep-Pak cartridges followed by preparative high-performance liquid chromatography. Negative ion chemical ionization mass spectrometry indicated that the two metabolites are the di- and mono-carboxylic acids resulting from oxidation of the terminal hydroxyl groups of the side chain(s). Mass spectral comparison of the urinary metabolites with synthetic compounds confirmed the identification.

Metabolism of viprostol--a synthetic vasodilator PGE2 analog.

Metabolic studies were done with 14C-Viprostol (I) administered by various routes (I.V., oral and topical) to six animal species and to man. Total radioactivity and metabolic profiles were analyzed in plasma, tissues and excreta. The main metabolites were isolated and identified by capillary GC/MS. Plasma and urinary metabolic profiles were qualitatively similar across species, with two major metabolic reactions being predominant: rapid hydrolysis to the pharmacologically active free acid (II) and oxidation of the alpha-chain to dinor and tetranor acids (III, IV). In the monkey and man, reduction of the 9-keto group lead to PGF2 type metabolites (VI-VIII). In the rat, omega oxidation of the beta-chain occurred as well, resulting in the formation of dicarboxylic acids (V).

Capillary gas chromatographic-mass spectrometric analysis of 15-deoxy-16-hydroxy-16-vinylprostaglandin E2.

A new topically active antihypertensive agent, the methyl ester of 15-deoxy-16-hydroxy-16-vinylprostaglandin E2 (1), rapidly hydrolyzes in blood to the carboxylic acid 2, which also has antihypertensive activity. A capillary gas chromatographic-mass spectrometric method is described for measuring 2 in human plasma or serum at expected experimental blood levels of 75-1500 pg/mL. The assay is based on selected-ion monitoring of the carboxylate anion formed from negative ion chemical ionization of the trimethylsilylpentafluorobenzyl ester of 2, using a trideuterated analogue of 2 as internal standard. The method has been used to analyze samples from subjects following topical application of 1-2 mg of 1. Sample preparation included isolation from 1 mL of plasma or serum and purification of the ester derivative with C18 cartridges, followed by a two-step trimethylsilylation.

1-Aryl-3-azabicyclo[3.1.0]hexanes, a new series of nonnarcotic analgesic agents.

A series of 1-aryl-3-azabicyclo[3.1.0]hexanes was synthesized by hydride reduction of 1-arylcyclopropanedicarboximides. Hydroxyphenyl analogues 20, 22, and 24 were prepared by EtSNa--DMF ether cleavage of the corresponding methoxyphenyl analogues 2m, 2n, and 23, respectively, with the secondary amines 20 and 22 going through the N-formyl intermediate 19 and 21. The p-ethoxy analogue 26 was obtained by O-ethylation of 19, followed by base hydrolysis of the amide 25. The greatest analgesic potency in mouse writhing and rat paw-pain assays was observed for para-substituted compounds. Bicifadine, 1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane (2b), was the most potent member of the series and is presently undergoing clinical trials in man. Analgesic activity of 2b is limited to the (+) enantiomer 2v, which has the 1R,5S absolute configuration as determined by single-crystal X-ray analysis. The N-methyl analogue (27d) of 2b showed significant analgesic potency, whereas the N-allyl (27a), N-(cyclopropylmethyl) (27b), and N-(n-hexyl) (27c) analogues were inactive. Bicifadine (2b) showed a nonnarcotic profile different from analogous azabicycloalkane and 3-phenylpyrrolidine analgesics.