Disposition, intestinal absorption and drug metabolizing enzyme activities after multiple doses of indomethacin in rat and effect of antacid and dicyclomine on the parameters.

Abstract

The effect of repeated treatment with indomethacin [antiinflammatory] (IND) on the disposition and intestinal absorption of the drug and microsomal drug-metabolizing enzyme activities were studied in comparison with coadministration of the drug and magnesium silicate or dicyclomine [an antispasmodic] in male Wistar rats. The plasma decay curve of IND following a rapid i.v. injection (6 mg/kg) was biexponential. The elimination rate constant (.beta.)of .beta. phase was 0.138 .+-. 0.015 h-1. The .beta. after the multiple dosing of IND (6 mg/kg per day for 7 d, p.o. [orally]) was significantly decreased as compared with that after a single dosing. In the multiple dose group coadministered magnesium silicate (0.6 g/kg), the AUC0 .fwdarw. .infin. [area under plasma concertration-time curve] was 2 times that after the multiple dosing of IND alone. The repeated administration (8 times every 6 h) with IND (4 mg/kg) alone and IND plus the antacid, respectively, gave the results similar to those in the multiple dosing. In the multiple treated group with IND alone, the drug-metabolizing enzyme activities were significantly decreased (32-43%) as compared with the control; however, the coadministration of magnesium silicate partly protected the decrease. The intestinal absorption rate constant of IND determined by in situ method was decreased after the multiple dosing of IND alone, but the constant was recovered to the control value after coadministration of the antacid. Following the multiple dosing of IND alone, the centrilobular necrosis in liver and a partial omission of the villi of intestinal epithelium were observed, but the concurrent dosing of magnesium silicate did not produce histopathological changes.