misoprostol and Kidney-Failure--Chronic

The disposition of misoprostol acid, the active metabolite of misoprostol, was studied in 48 subjects with various degrees of renal function after administration of a single 400 microgram oral dose of misoprostol. Subjects were assigned to one of four treatment groups: group 1, normal renal function with creatinine clearance (CLCR) 80-140 mL/min/1.73 m2; group 2, mild renal impairment with CLCR 50-79 mL/min/1.73 m2; group 3, moderate renal impairment with CLCR 20-49 mL/min/1.73 m2 or group 4, end stage renal disease (ESRD) patients maintained on hemodialysis. The maximum plasma concentration (Cmax) and time to reach Cmax (tmax) for misoprostol acid tended to be larger in group 4 subjects; however, it failed to reach statistical significance. Although not statistically significant, in group 4 subjects the terminal half-life (t1/2) of misoprostol acid was almost twice as large (1.27 +/- 0.77 h) as in groups 1, 2, and 3 (0.70 +/- 0.72, 0.72 +/- 0.67, and 0.73 +/- 0.45 h, respectively). Misoprostol acid's total area under the plasma concentration curve (AUC0 infinity) was larger in group 4 subjects (1173.5 +/- 487.4 pg.h/mL) as compared with groups 1, 2, and 3 (421.4 +/- 263.1, 418.9 +/- 114.5, and 377.0 +/- 145.2 pg.h/mL, respectively; P < .05). The apparent total body clearance (CL) of misoprostol acid was statistically significantly smaller in group 4 subjects (0.094 +/- 0.044 L/kg/min) as compared only with group 3 subjects (0.284 +/- 0.102 L/kg/min). The dose of misoprostol may need to be reduced in ESRD patients on prolonged hemodialysis to prevent unnecessary high plasma levels of misoprostol acid and to avoid possible dose-related adverse effects.

Topics: Acute Kidney Injury; Creatinine; Female; Half-Life; Humans; Kidney; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Misoprostol; Renal Insufficiency

Prostaglandins of the E series (PGE) are known to contribute to the maintenance of renal hemodynamics in subjects with chronic renal insufficiency. Agents that block PGE synthesis, nonsteroidal anti-inflammatory agents (NSAID), are widely used by people with renal insufficiency. This study was undertaken in subjects with renal insufficiency secondary to diabetes to evaluate the acute effects of a PGE1 analog, misoprostol, on NSAID-induced changes in RBF, as calculated by para-aminohippurate clearance, and GFR, as calculated by inulin clearance. Sodium excretion was also assessed. Twenty-five fasting subjects with a mean age of 56 +/- 4 yr received 800 mg of ibuprofen orally. A concomitant dose of either a placebo (PL) or 200 micrograms of misoprostol was also given. This was followed in 1 h by either a placebo or an additional 200-micrograms dose of misoprostol. Measurements for the determination of RBF, GFR, blood pressure, and fractional excretion of sodium were performed every 30 min for the next 5 h. The greatest reduction in both GFR (-25 +/- 7 mL/min per 1.73 m2 PL versus -10 +/- 4 mL/min per 1.73 m2, misoprostol delta GFR; P < 0.05) and RBF (-48 +/- 21 mL/min per 1.73 m2 PL versus -15 +/- 8 mL/min per 1.73 m2, M delta RBF; P < 0.05) occurred approximately 2 h after the NSAID dose. No significant differences were noted in blood pressure, fractional excretion of sodium, or other measured parameters between groups during the entire study. Gastrointestinal upset was the most common side effect observed in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Diabetic Nephropathies; Double-Blind Method; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Ibuprofen; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Misoprostol; Placebos; Renal Circulation

The pharmacokinetics of misoprostol were examined in the following contexts: in coadministration with the nonsteroidal antiinflammatory agents (NSAID) aspirin, diclofenac, ibuprofen, indomethacin and piroxicam; in coadministration with agents extensively metabolized by the liver--i.e., antipyrine, propranolol and diazepam; in healthy elderly subjects; and in patients with various degrees of renal failure. No clinically important interactions between misoprostol and NSAID were observed. Similarly, no metabolic interactions between misoprostol and antipyrine, propranolol or diazepam were noted. Pharmacokinetic variable values in elderly subjects did not differ in a clinically significant manner from those in younger subjects. Finally, although values for some pharmacokinetic variables--maximum concentration of misoprostol acid, area under the concentration-time curve and elimination half-life--were increased in patients with renal failure compared with controls, these alterations do not warrant changes in misoprostol dosage. These factors are particularly relevant to safety of misoprostol administration in elderly individuals, who not only consume more NSAID than young adults, but are also more likely to have intercurrent nonarthritic illness requiring additional medication and potentially modifying drug kinetics.

Topics: Adult; Aged; Aging; Alprostadil; Anti-Inflammatory Agents, Non-Steroidal; Antipyrine; Diazepam; Drug Interactions; Humans; Kidney Failure, Chronic; Liver; Misoprostol; Propranolol