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The excretion balance and the urinary metabolism of indobufen (+/- 2-[p-(1-oxo-2-isoindolinyl)-phenyl] butyric acid), a platelet aggregation inhibitor, has been studied in rats and mice after oral administration. The urinary metabolic profile of indobufen exhibited a marked species difference. The major metabolic pathway in the mouse was acyl glucuronidation followed by renal excretion, whereas in rats, 5-hydroxylation and subsequent sulphation at the introduced hydroxyl group predominated. Comparison of these results with previous data obtained in humans indicates that the mouse, and not the rat, is the rodent species of choice to be considered in the study of this compound.

The plasma pharmacokinetics and urinary elimination of the enantiomers of indobufen (2-[p-(1-oxo-2-isoindolinyl)-phenyl]butyric acid), a novel platelet aggregation inhibitor, have been studied in male healthy volunteers given either the racemic compound or the S-enantiomer (200 mg racemate, 100 mg S-enantiomer). Enantiospecific analysis of indobufen in plasma and urine was achieved by HPLC of its L-leucinamide diastereoisomers. After administration of the racemate, the pharmacokinetic behaviour of the R- and S-enantiomers differed, the plasma levels of the S form declining more rapidly [half-lives = 6.2 hr (S), 8.7 hr (R)]. No substantial differences were observed in terms of plasma level profile of S-indobufen when administered alone and in the racemic mixture. A statistically significant difference between the two enantiomers after administration of the racemate was found in the area under the curve (AUC), peak plasma levels (Cmax) and elimination half-life (t1/2 beta) whereas no statistically significant difference was detected in the time of peak (tmax). When the pharmacokinetic parameters Cmax, AUC, t1/2 beta and tmax of S-indobufen administered alone or as racemate were compared, there were no statistically significant differences between treatments as well as between periods and sequences. The urinary excretion of total S-indobufen (free + glucuronide) and of total R-indobufen after administration of the racemate was essentially the same. No difference was observed either in the urinary excretion of total S-indobufen after administration of the racemate or of the S-enantiomer.

The plasma pharmacokinetics and urinary elimination of the enantiomers of indobufen, a novel platelet aggregation inhibitor, have been studied in rats and mice given either the racemic compound or the individual enantiomers (rat 8 mg/kg racemate, 4 mg/kg enantiomers; mouse 25 mg/kg racemate, 12.5 mg/kg enantiomers). Enantiospecific analysis of indobufen in plasma and urine was achieved by HPLC of its L-leucinamide diastereoisomers. In rat, the two enantiomers have very different plasma elimination half lives (S, 3.9 hr; R, 12.2 hr), irrespective of the optical form administered. The plasma concentration-time curves of S-indobufen were identical after racemic or S-indobufen, but the plasma levels of R-indobufen were lower after the R-enantiomer than after the racemate. Urinary recovery of free and conjugated indobufen was less than 3% of the dose, independent of the optical form administered. In the mouse, R-indobufen was cleared from plasma more rapidly than its S-antipode (elimination T1/2 R, 2.5 hr; S, 3.8 hr) but differences were smaller than those seen in the rat. The plasma concentration-time curves of the S-enantiomer were the same after racemic or S-indobufen, but levels of its R-antipode were much lower when it was given alone than after administration of the racemate. The urinary recovery of free and conjugated indobufen also exhibited enantioselectivity, with preferential elimination of the S-enantiomer.