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 reducti on of LOPOX to LCP was investigated to provide a pharmacokinetic basis for the pharmacodynamics and improved side effect profile of the prod rug. Reduction of LOPOX was studied in vitro in gut contents, gut flor a, intestinal cells, and hepatocytes. In vivo pharmacokinetics and met abolism of LOPOX and LOP were compared in the dog. LOPOX could be effi ciently reduced in the gut contents of rats, dogs, and humans, with th e most extensive reduction found in cecal contents. Reduction was dimi nished to 13% of the anaerobic LOPOX reductase activity in the presenc e of oxygen and to 2.5% of the original activity by heat treatment of the contents. In human ileal effluents, LOPOX reductase activity was s imilar 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 p art of the intestine. In the dog, there was a gradual increase in LOPO X reductase activity from the proximal small intestine toward the cecu m. In germ-free rats, the cecum contained <1% of the activity of the s mall intestine. Isolated intestinal microflora of rat and dog was able to reduce LOPOX to LOP under anaerobic conditions, indicating that th e microflora was primarily involved in the reduction. In its absence ( i.e. in germ-free rats), reduction could still be conducted by other u nknown components of the gut contents. In isolated intestinal cells, t he initial rate of drug uptake was similar to 3-10 times faster for LO P than for LOPOX. The rate of reduction in the cells paralleled the ce llular uptake of the radioactivity after incubation with [H-3]LOPOX. T he results of these in vitro studies indicate that oral administration of LOPOX should result in lower systemic availability and higher conc entrations of LOP in the distal regions of the gut. This was confirmed in vivo after oral and intravenous administrations of either compound to the dog. Peak portal vein concentrations and portal AUC(0-120 min) values of LOP were 5-6 times lower after administration of LOPOX than after LOP itself. After oral administration of LOP, peak levels in pl asma, obtained after puncture of the left jugular vein and therefore r epresenting systemic concentrations, amounted to 2.41 ng/ml, whereas a fter administration of LOPOX, peak plasma levels of metabolically form ed LOP were only 1.1 ng/ml. The absolute systemic availability of the active drug LOP after oral administration of LOP itself was 18.8%, whe reas it was 10.5% after the administration of LOPOX. In addition, the fecal excretion of LOP after an oral dose of the prodrug (and 9% of th e dose) was similar to 10 times more abundant than after an oral dose of LOP itself (1% of the dose). In conclusion, the results indicate th at LOPOX can be regarded as a site-specific prodrug that acts as a che mically designed controlled-release formulation of LCP, which most pro bably will result in a more even exposure of a greater length of the i ntestinal wall to the active drug. Therefore, it is to be expected tha t the prodrug LOPOX, when compared with LOP, will have adequate antidi arrheal activity at lower doses and an improved side-effect profile.