Effects of Indomethacin on the Pharmacokinetics and Pharmacodynamics of Prednisolone in Rats

Abstract

The effect of indomethacin on the disposition of prednisolone and the induction of tyrosine aminotransferase (TAT) was examined in male Sprague‐Dawley rats. Rats were pretreated with either indomethacin (5 mg/kg, intraperitoneally) or phosphate buffered saline (control) twice daily for 6 days followed by a single dose of prednisolone. Blood samples were collected after prednisolone administration. In separate animals, hepatic TAT activity (pharmacologic effect) was measured 4 h after the prednisolone dose. In addition, the effect of indomethacin on thein vitroprotein binding of prednisolone was examined in pooled rat and human plasma. The clearance and apparent volume of distribution of prednisolone in the control and indomethacin‐treated animals were similar, averaging 4.71 versus 4.05 L/h/kg and 1.37 versus 1.33 L/kg, respectively. The elimination half‐life was 0.48 h in both groups. Indomethacin also did not affect the protein binding of prednisolone in rat or human plasma. However, indomethacin pretreatment increased the hepatic TAT activity induced by prednisolone. These studies indicate that indomethacin may affect the pharmacological effects of prednisolone without influencing its pharmacokinetics.