Sulindac kinetics and effects on renal function and prostaglandin excretion in renal insufficiency

The purpose of this study was to evaluate the pharmacokinetics of sulindac, a purported 'renal sparing' nonsteroidal anti-inflammatory drug, and its effects on renal function and prostaglandin excretion in patients with reduced glomerular filtration rate. Twelve female patients (glomerular filtration rate 37 ± 4 mL/min) were treated with sulindac 200 mg bid for 11 days. Urinary PGE₂, 6-keto-PGF(1α), and serum thromboxane (TxB₂) generation were measured by radioimmunoassay (RIA) following extraction on C-18 columns. Glomerular filtration rate and effective renal plasma flow were measured by ⁹⁹TC-DPTA and ¹³¹I-para-aminohippuric acid clearance. In six patients serum and urine levels of sulindac and its metabolites were measured by high-pressure liquid chromatography (HPLC). Sulindac was rapidly absorbed and converted to sulindac sulfide with peak levels 2 hours after a single dose, but steady state levels were not reached prior to drug discontinuation. Sulindac sulfide AUC (0-5 hours μg min/mL) progressively increased from 382 to 3,030 on day 11. It did not appear in the urine. Baseline urinary PGE₂ and 6-keto-PGF(1α) excretion were 23.8 ± 5.6 and 18.9 ± 2.7 ng/hr respectively and were reduced by 68% and 47% by day 4 of therapy. TxB₂ generation fell by 34% after one dose and by 67% by day 11. There was a significant increase in serum creatinine from 1.88 ± 0.13 mg/dl before treatment to 2.16 ± 0.15 mg/dL (P <.05) after eleven days. There was a significant (P <.001) decrease in effective renal plasma flow, 184.9 ± 16.3 mL/min before therapy vs 164.1 ± 17.0 mL/min on day 11 of therapy. Glomerular filtration rate (GFR) was significantly reduced following 4 days of therapy (P <.05: day 1 vs day 4) but by day 11 had returned to baseline. We concluded than in this population the active sulindac sulfide metabolite accumulates systemically and can significantly inhibit renal prostaglandin metabolism as well as peripheral TxB₂ generation and may effect renal function.