RENAL CARBONIC ANHYDRASE INHIBITION BY BENZOLAMIDE (CL 11,366) IN MAN

¹ Departments of Pharmacology and Medicine, University of Florida College of Medicine, Gainesville, Florida

The human pharmacology of benzolamide (CL 11,366), a new carbonic anhydrase inhibitor with predominant renal action, was studied in two healthy men and eight men with obstructive lung disease. Drug was given in doses of 1.5 to 5 mg/kg p.o. Inhibitor concentrations reached a peak in plasma at 2 to 4 hr but not, at these doses, in red cells for 1 day or more. Decay of inhibitor in plasma proceeded with a half-life averaging 4 hr and, in red cells, 5 days. Urinary recovery of inhibitor was 16 to 52% of oral doses in the first 24 hr and averaged 31%. A dose of 3 mg/kg p.o. produced a full bicarbonate diuresis with increased excretion of sodium and potassium. The resulting metabolic acidemia was sustained on repeated dosage every 12 hr. Major systemic effects were reductions in plasma bicarbonate (by 4-5 mM), blood pH, arterial and mixed venous CO₂ tensions and raising of arterial O₂ tension. There was no evidence of interference with red cell carbonic anhydrase activity at doses employed. Side effects were minimal or absent. No adverse effects on pulmonary function occurred during treatment. Improvements were observed in vital capacity and, in three patients tested, in exercise tolerance, but the contribution of treatment was not determined. It appears that benzolamide may be used to inhibit renal carbonic anhydrase in man and to exclude nonrenal actions such as erythrocytic inhibition and possibly side effects.