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The Pharmacokinetics and Pharmacodynamics of a New Thromboxane Synthetase Inhibitor, 6‐(1‐Imidazolylmethyl)‐5,6,7,8‐tetrahydronaphthalene‐2‐carboxylic acid (DP‐1904), in Man after Single Oral Administration

The pharmacokinetics of DP‐1904, a new potent and selective thromboxane synthetase inhibitor and its effects on ex‐vivo prostanoid formation were studied in Japanese normal male volunteers, who received orally a single 10, 20, 50, 100, 200, 400 or 800 mg dose. The drug was well tolerated by all subjects without evidence of any adverse reactions. The absorption of DP‐1904 from gastro‐intestinal tract was rapid. After oral doses of 10–800 mg of the drug given to volunteers in the fasted state, the mean maximum drug concentrations in plasma (Cmax) (mean ± s.e., n = 5) of 0·215 (± 0·041), 0·399 (± 0·037), 1·47 (± 0·22), 2·86 (±0·22), 4·66 (±0·58), 7·28(±0·72) and 16·9 (±2·6) μgmL−1 were reached within 1 h. DP‐1904 concentrations declined monophasically after Cmax with half lives of 30–40 min. These half lives were independent of the administered doses. The mean area under the concentration‐time curves (AUCs) increased from 0·398 (±0·038) to 30·0 (±2·7) μgh. mL−1 as the dose increased from 10 to 800 mg. Linear relations between the doses and Cmax and AUCs were observed. The correlation coefficients for Cmax and AUC were 0·930 and 0·960, respectively. The apparent oral clearance (CL/F) and renal clearance (CLR) did not change significantly as dose increased from 10 to 800 mg. The kinetics of DP‐1904 proved to be linear in the dose range studied. The urinary excretion of DP‐1904 was also independent of the administered dose, and about half of the dose was recovered in urine as unchanged form within 48 h after administration. The elimination of the drug was fast and almost complete within 6 h after dosing. On the other hand, only 0·5% of the dose was excreted into faeces as intact DP‐1904 up to 48 h after 400 mg oral dose. Food intake delayed the absorption of DP‐1904 but did not significantly modify its pharmacokinetics. Serum thromboxane B2 levels (the stable metabolite of thromboxane A2) were reduced more than 90% within 0·5 h after all doses studied. DP‐1904 had a long duration of inhibitory activity and there was still more than 80, 90 and 95% suppression at 12 h after 200, 400, and 800 mg doses, respectively.