Single oral doses of 600 mg of 14C-labelled gamma-oxo(1,1'-biphenyl)-4-butanoic acid (fenbufen) were administered to three male volunteers. Additional male and female subjects received single (500-700 mg) or multiple (300-400 mg b.i.d.) doses of non-isotopically labelled drug. Fenbufen was rapidly absorbed from the gastroiintestinal tract to the extent of at least 78%. Food reduced the rate but not the extent of absorption. Peak serum concentrations of total drug related compounds were reached by 2 h, at which time fenbufen accounted for only 11% of these substances. The remaining drug related material consisted of two metabolites: gamma-hydroxy(1,1'-biphenyl)-4-butanoic acid and (1,1'-biphenyl)-4-acetic acid. Steady state serum concentrations were reached within a week with multiple dosing regimens. The ratio of fenbufen to its circulating metabolites did not change over a month of daily dosing. Only traces of fenbufen and metabolites were present in the cellular components of blood or in human milk, but significant amounts (concentrations one-third those in serum) were measured in the synovial fluid of arthritic patients. Fenbufen and its circulating metabolites were highly bound (> 98%) to human serum in vitro, but at therapeutic levels showed very small or no effects on the serum binding of various other commonly used drugs. Concomitant administration of fenbufen and acetylsalicylic acid (ASA) resulted in decreased serum concentration of fenbufen and its metabolites compared to those obtained from fenbufen administration alone. In addition to the serum metabolites, three more transformation products were identified in urine: 4'-hydroxy(1,1'-biphenyl)-4-acetic acid, gamma,4'-dihydroxy(1,1'-biphenyl)-4-butanoic acid and beta, gamma-dyhydroxy(1,1'-biphenyl)-4-butanoic acid.

Absorption, distribution, metabolism and excretion studies with gamma-oxo-(1,1'-biphenyl)-4-butanoic acid (fenbufen) have been conducted in several laboratory animal species. Single oral doses of 14C-fenbufen were administered to rats, guinea pigs, rabbits and dogs (10, 40 and 100 mg/kg) and to mice and monkeys (40 and 100 mg/kg); rats, rabbits and dogs received an i.v. dose of 10 mg/kg. Multiple oral doses of 40 mg/kg of non-radiolabelled fenbufen were studied in the rat and dog. Plasma concentrations of fenbufen and its metabolites were dose dependent with areas under the curve showing general linearity both within and among species over the range studied (10--100 mg/kg). Radioactivity was present in all tissues examined following a dose of 10 mg/kg 14C-fenbufen orally to rats and guinea pigs. Except for gastrointestinal tract, liver and kidney these tissue levels were usually lower than the corresponding plasma level through 24 h post dose. The major drug-related material in plasma of the rat, guinea pig and dog was (1,1'-biphenyl)-4-acetic acid; in the monkey it was gamma-hydroxy(1,1'-biphenyl)-4-butanoic acid. These two compounds together with unchanged fenbufen were present in the plasma of all the animals studied. In addition 4'-hydroxy(1,1'-biphenyl)-4-acetic acid was found in rat plasma and beta, gamma-dihydroxyl(1,1'-biphenyl)-4-butanoic acid in dog plasma. The plasma profiles of fenbufen and metabolites did not change during multiple, daily oral doses of 40 mg/kg in either the rat (up to 10 days) or the dog through 18 months. In varying proportions, a total of 11 metabolites (including those listed above) together with fenbufen itself were isolated and characterized from the urine of mice, rats, guinea pigs, dogs and/or monkeys dosed with fenbufen. Within each of the species studied, excretion patterns of drug-related materials in the urine and feces following an i.v. dose were similar to those following the oral doses. In general urine was the major excretory pathway.

Specific procedures are described for the determination of fenbufen and its metabolites in serum and urine using high-pressure liquid chromatography. Serum or urine extracts were chromatographed on a bounded reversed-phase partitioning column. The sensitivity of the assay for fenbufen was 0.5 microgram/ml in serum with 2-ml samples and 1.0 microgram/ml in urine with 1-ml samples. The procedures are suitable for bioavailability and pharmacokinetic studies.

An aminocyclitol antibiotic, LL-BM408, discovered in our screening program for new antibiotics, was produced by an undetermined species of Streptomyces, which also produced paromomycin I and paromomycin 11. A purified sample of LL-BM408 was found to have activity against gram-negative bacterial infections in mice. LL-BM408 was identified as ribosyl paromamine (I) based on identification of acid hydrolysis fragments, nmr and mass spectral analyses. Although ribosyl paromamine was prepared by chemical degradation of antibiotic BU-1709E22) and paromomycin,3) this appears to be the first time that it has been detected as a direct fermentation product. LL-BM408 was produced by the fermentation of the organism on a medium containing dextrose, glycerol, soy flour, sodium chloride and calcium carbonate. The course of antibiotic production was followed by inhibition of Klebsiella pneumoniae by the cup agar-diffusion method.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStructure of mitiromycinGeorge O. Morton, George E. Van Lear, and William FulmorCite this: J. Am. Chem. Soc. 1970, 92, 8, 2588–2590Publication Date (Print):April 1, 1970Publication History Published online1 May 2002Published inissue 1 April 1970https://pubs.acs.org/doi/10.1021/ja00711a085https://doi.org/10.1021/ja00711a085research-articleACS PublicationsRequest reuse permissionsArticle Views64Altmetric-Citations11LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts