Reduction of the prodrug loperamide oxide to its active drug loperamide in the gut of rats, dogs, and humans.

Loperamide oxide (LOPOX) is a prodrug of loperamide (LOP). The reduction of LOPOX to LOP was investigated to provide a pharmacokinetic basis for the pharmacodynamics and improved side effect profile of the prodrug. Reduction of LOPOX was studied in vitro in gut contents, gut flora, intestinal cells, and hepatocytes. In vivo pharmacokinetics and metabolism of LOPOX and LOP were compared in the dog. LOPOX could be efficiently reduced in the gut contents of rats, dogs, and humans, with the most extensive reduction found in cecal contents. Reduction was diminished to 13% of the anaerobic LOPOX reductase activity in the presence of oxygen and to 2.5% of the original activity by heat treatment of the contents. In human ileal effluents, LOPOX reductase activity was similar in oxygen and heat sensitivity. In the rat, the cecum contained on average 89.2% of the total activity in the contents of the upper part of the intestine. In the dog, there was a gradual increase in LOPOX reductase activity from the proximal small intestine toward the cecum. In germ-free rats, the cecum contained < 1% of the activity of the small intestine. Isolated intestinal microflora of rat and dog was able to reduce LOPOX to LOP under anaerobic conditions, indicating that the microflora was primarily involved in the reduction. In its absence (i.e. in germ-free rats), reduction could still be conducted by other unknown components of the gut contents. In isolated intestinal cells, the initial rate of drug uptake was approximately 3-10 times faster for LOP than for LOPOX.(ABSTRACT TRUNCATED AT 250 WORDS)