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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.

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.

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.