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Gemfibrozil or 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid is a novel hypolipemic agent (Creger 1972). Unlike other aryloxyalkanoic acids such as clofibric acid (Thorp 1963), Win 35833 (Davison et al. 1975) and halofenate (Hucker et al. 1971), gemfibrozil undergoes extensive metabolism in animals (Okerholm et al. 1976) and in man. Materials and MethodsGemfibrozil-3H was prepared by a catalytic exchange with tritium gas in the presence of 5% rhodium on alumina (New England Nuclear Corporation). It was purified by preparative thinlayer chromatography. For all animal experiments, gemfibrozil-3H was mixed with unlabelled gemfibrozil and dissolved in a 10% excess of 1 N sodium hydroxide. This solution was administered by intubation. The human dose was prepared by dilution of the tritium-labelled material with unlabelled gemfibrozil, crystallization to constant specific activity (0.377 ,Ci/mg) and 200 mg portions were packed into gelatin capsules. Non-volatile tritium was determined by pipetting duplicate aliquots of plasma, red blood cells, urine, bile and fecal homogenates into cellophane bags, air-drying the samples and combusting in a Packard Oxidizer. The resulting tritiated water was mixed with scintillator and analysed by counting in a Packard Tri-Carb spectrometer. The resulting counts per minute were converted into disintegrations per minute by external standardization. Thin-layer chromatography (TLC) was performed by spotting extracts of plasma, urine or bile on silica gel GF plates which were then developed in benzene :ethyl acetate :acetic acid (65:35:2, v/v/v). The plates were then scraped in 0.5 cm sections, eluted with 2 ml of methanol, mixed with scintillator and counted as described above.

A competitive protein binding assay for norethindrone was developed to measure plasma levels in human subjects. The plasma levels were considerably higher in women than in men, especially at low dose levels. The plasma levels were directly related to the dose in men; but greater variations in the plasma levels were observed in women. The plasma half-life was about 5 h in both sexes with single oral doses of 5 to 20 mg. A comparative bioavailability study with norethindrone from 2 different manufacturers, formulated in the same manner, showed no significant differences in absorption characteristics and provided sufficient data for pharmacokinetic analysis.

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