Bioavailability of indomethacin calcium and magnesium, and effect of the salts on drug metabolizing enzyme activities in rats.

Abstract

To clarify the mechanism of enhanced absorption of indomethacin (IND) when dosed with magnesium silicate, reported previously, magnesium (IND-Mg) and calcium (IND-Ca) salts of IND were prepared, and the bioavailability in rat and physical properties of these salts were studied in comparison with IND. The mean plasma levels after a single oral dosing of IND-Ca and IND-Mg were significantly higher than those after IND (6 mg/kg). The absolute bioavailability calculated was 63.7% for IND, 83.2% for IND-Mg and 96.8% for IND-Ca. The area (AUC) under the plasma concentration curve after multiple oral dosing of IND-Ca and IND-Mg was also significantly larger than that after IND multiple dosing (p less than 0.001). Thus, the increased absorption of the salts made it possible to decrease their dosage. The mean plasma levels and the AUC after multiple dosing of the salts in the decreased doses (4.16 mg/kg for IND-Ca and 4.74 mg/kg for IND-Mg) were significantly high as compared with those in IND dose (6 mg/kg) group (p less than 0.05). In IND-salt multiple dose groups, the drug-metabolizing enzyme activities were only slightly decreased as compared with the control, while activities in IND dose group were substantially decreased. There was no significant change in the plasma protein binding between the IND- and the salt-treated rats. The partition coefficient (n-octanol-water) for IND-Ca and IND-Mg was higher than that of IND. The rank order of solubility in 2% taurocholate solution was IND-Mg greater than IND greater than IND-Ca, and the solubility of IND-Mg was 3 times higher than that of IND-Ca. Therefore, the mechanism of increased absorption of these salts was probably ascribed to the enhanced lipid solubility and increased solubility in bile and intestine juice.