Purpose: 1. To compare the disposition of tracer morphine ([3H]M) following systemic and intraduodenal administration in the recirculating, rat small intestine preparation in absence or presence of verapamil (V), an inhibitor of P-glycoprotein. 2. To develop a physiological model to explain the observations.
Methods: A bolus dose of [3H]M was added to the reservoir or injected into the duodenum of the rat small intestine preparation. V (200 microM in reservoir) was either absent (control studies) or present. Intestinal microsomal, incubation studies were performed to evaluate the effect of V on morphine glucuronidation.
Results: After systemic administration, [3H]M was not metabolized but was exsorbed into lumen. By contrast, both [3H]M and the 3beta-glucuronide metabolite, [3H]M3G, appeared in reservoir and lumen after intraduodenal administration. A physiologically-based model that encompassed absorption, metabolism and secretion was able to describe the route-dependent glucuronidation of M. The presence of V resulted in diminished levels of M3G in perfusate and lumen and mirrored the observation of decreased glucuronidation in microsomal incubations. Verapamil appeared to be an inhibitor of glucuronidation and not secretion of M.
Conclusions: M was secreted and absorbed by the rat small intestine. Route-dependent glucuronidation of M was explained by physiological modeling when M was poorly partitioned in intestinal tissue, with a low influx clearance from blood and a even poorer efflux clearance from tissue. The poor efflux rendered a much greater metabolism of M that was initially absorbed from the lumen. V increased the extent of M absorption through inhibition of M glucuronidation.