Effect of ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney

ABSTRACT Non‐steroidal anti‐inflammatory drugs (NSAIDs) have been shown to inhibit the renal tubular secretion of methotrexate. However, the relative contribution of the active S‐ and inactive R‐enantiomers is unknown. This study examined the effect of racemic ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney (IPK). Nineteen kidneys were divided between a control and three treatment groups. Controls were perfused with methotrexate alone (25 μg mL−1, n = 5) over three 30‐min periods. Treatment groups were perfused with methotrexate (25 μg mL−1) for the first period, followed by a second period of methotrexate (25 μg mL−1) plus R‐ (n = 5), S‐ (n = 5) or RS‐ketoprofen (n = 4) at 25 μg mL−1, and a third period of methotrexate (25 μg mL−1) plus R‐, S‐ or RS‐ketoprofen (50 μg mL−1). Perfusate and urine were collected over 10‐min intervals. Methotrexate was measured by HPLC and its binding in perfusate by ultrafiltration. The clearance ratio (CR) for methotrexate was obtained by dividing the renal clearance by the product of its fraction unbound and the glomerular filtration rate. During control experiments, there was no significant change in the CR over 90 min. R‐, S‐ and RS‐ketoprofen at 50 μg mL−1 reduced the CR of methotrexate significantly, but there was no difference between the three groups. While the enantiomers of ketoprofen reduced the renal excretion of methotrexate, the interaction was not enantioselective.