Comparison of the effects of sulindac with other cyclooxygenase inhibitors on prostaglandin excretion and renal function in normal and chronic bile duct-ligated dogs and swine

Abstract

Sulindac sulfoxide is a prodrug which must be converted to a reduced active metabolite, sulindac sulfide, in order to inhibit arachidonate cyclooxygenase. Oral administration of sulindac sulfoxide does not yield substantial amounts of sulindac sulfide in the urine. To determine whether sulindac sulfide inhibits renal prostaglandin (PG) synthesis, the active form of the drug, sulindac sulfide (5 mg/kg i.v.), was administered to four sham-ligated dogs and four dogs with liver disease induced by chronic (6 weeks) common bile duct ligation (CBDL). In both the sham and CBDL animals the sulindac sulfide caused a 60 to 90% reduction in PGE2, PGF2 alpha and 6-keto-PGF1 alpha excretion rates. In the same animals, subsequent treatment with another cyclooxygenase inhibitor, naproxen (10 mg/kg i.v.), did not result in any further decrease in PGE2 or PGF2 alpha excretion but did decrease 6-keto-PGF1 alpha excretion. In the CBDL animals, sulindac sulfide treatment decreased renal blood flow, glomerular filtration rate and urine volume and resulted in the urinary excretion of large amounts of the sulindac sulfide. Similar changes in PG excretion and renal function were observed in CBDL animals treated solely with naproxen (10 mg/kg i.v.) or with ibuprofen (20 mg/kg i.v.). In four normal and three CBDL animals, we determined that i.v. administration of the prodrug, sulindac sulfoxide (5-15 mg/kg), resulted in plasma levels of 2-5 micrograms/ml of the active drug, sulindac sulfide, only in the CBDL animals. In subsequent experiments, we gave sulindac sulfoxide, 5 mg/kg i.v., to five CBDL dogs and three CBDL miniature swine.(ABSTRACT TRUNCATED AT 250 WORDS)