Pharmacokinetics and metabolism of diphenoxylate in man

The absorption, excretion, and biotransformation of 14C-diphenoxylate hydrochloride (5 mg. containing 20.2 µc of 14C) when administered orally in ethanolic solution and without the presence of atropine sulfate was studied in 3 men. The mean urinary and fecal excretion of the total label in a 96 hour period was 13.65 ± 1.18 per cent and 49.20 ± 2.24 per cent, respectively. Thin-layer radiochromatographic analysis of the label in excreta indicated extensive biotransformation of the parent drug. In the urine, the maior metabolites were characterized as diphenoxylic acid and hydroxydiphenoxylic acid. These acids were present in both the free and coniugated fractions. Radioactivity in the plasma was associated largely with diphenoxylic acid and to a smaller extent with the unchanged drug. Pharmacokinetic analysis using a one-compartment open model showed a rapid absorption (t½ = 19.7 ± 1.7 minutes; peak level at 2.0 hours) of diphenoxylate followed by its rapid elimination (t½ = 2.50 ± 0.34 hours). The plasma half-life (t½ = 4.38 ± 1.04 hours) of diphenoxylic acid was higher than that of diphenoxylate.