Route-dependent metabolism of morphine in the vascularly perfused rat small intestine preparation

Purpose. 1. To compare the disposition of tracer morphine ([H-3]M) followin g systemic and intraduodenal administration in the recirculating, rat small intestine preparation in absence or presence of verapamil (V), an inhibito r of P-glycoprotein, 2. To develop a physiological model to explain the obs ervations. Methods. A bolus dose of [H-3]M was added to the reservoir or injected into the duodenum of the rat small intestine preparation. V (200 mu M in reserv oir) 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, [H-3]M was not metabolized but was exsorbed into lumen. By contrast, both [H-3]M and the 3 beta-glucuronide me tabolite, [H-3]M3G, appeared in reservoir and lumen after intraduodenal adm inistration. A physiologically-based model that encompassed absorption, met abolism and secretion was able to describe the route-dependent glucuronidat ion of M. The presence of V resulted in diminished levels of M3G in perfusa te and lumen and mirrored the observation of decreased glucuronidation in m icrosomal incubations. Verapamil appeared to be an inhibitor of glucuronida tion and not secretion of M. Conclusions. M was secreted and absorbed by the rat small intestine. Route- dependent glucuronidation of hi was explained by physiological modeling whe n M was poorly partitioned in intestinal tissue, with a low influx clearanc e from blood and a even poorer efflux clearance from tissue. The poor efflu x 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 g lucuronidation.