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Route-Dependent Metabolism of Morphine in the Vascularly Perfused Rat Small Intestine Preparation

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Abstract

Purpose. 1. To compare the disposition of tracer morphine ([3H]M)following systemic and intraduodenal administration in therecirculating, rat small intestine preparation in absence or presence of verapamil(V), an inhibitor of P-glycoprotein. 2. To develop a physiological modelto explain the observations.

Methods. A bolus dose of [3H]M was added to the reservoir or injectedinto the duodenum of the rat small intestine preparation. V (200 μMin reservoir) was either absent (control studies) or present. Intestinalmicrosomal, incubation studies were performed to evaluate the effectof V on morphine glucuronidation.

Results. After systemic administration, [3H]M was not metabolizedbut was exsorbed into lumen. By contrast, both [3H]M and the3β-glucuronide metabolite, [3H]M3G, appeared in reservoir and lumenafter intraduodenal administration. A physiologically-based model thatencompassed absorption, metabolism and secretion was able to describethe route-dependent glucuronidation of M. The presence of V resultedin diminished levels of M3G in perfusate and lumen and mirrored theobservation of decreased glucuronidation in microsomal incubations.Verapamil appeared to be an inhibitor of glucuronidation and notsecretion of M.

Conclusions. M was secreted and absorbed by the rat small intestine.Route-dependent glucuronidation of M was explained by physiologicalmodeling when M was poorly partitioned in intestinal tissue, with alow influx clearance from blood and a even poorer efflux clearancefrom tissue. The poor efflux rendered a much greater metabolism ofM that was initially absorbed from the lumen. V increased the extentof M absorption through inhibition of M glucuronidation.

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Authors and Affiliations

  1. Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 2S2

    Margaret M. Doherty

  2. Victoria College of Pharmacy, Monash University, Victoria, Australia

    Margaret M. Doherty

  3. Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, M5S 2S2, Canada

    K. Sandy Pang

  4. Victoria College of Pharmacy, Monash University, Victoria, Australia

    K. Sandy Pang

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  1. Margaret M. Doherty
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This work was supported by the Medical Research Council of Canada (MA9104 and MOP-36457) and was presented in part at the ASPET meeting in San Diego, 1997 and the AAPS meeting in Boston, 1997.

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Doherty, M.M., Pang, K.S. Route-Dependent Metabolism of Morphine in the Vascularly Perfused Rat Small Intestine Preparation. Pharm Res 17, 291–298 (2000). https://doi.org/10.1023/A:1007548905772

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