Segmental-dependent membrane permeability along the intestine following oral drug administration: Evaluation of a triple single-pass intestinal perfusion (TSPIP) approach in the rat.
In this paper we evaluate a modified approach to the traditional single-pass intestinal perfusion (SPIP) rat model in investigating segmental-dependent permeability along the intestine following oral drug administration. Whereas in the traditional model one single segment of the intestine is perfused, we have simultaneously perfused three individual segments of each rat intestine: proximal jejunum, mid-small intestine and distal ileum, enabling to obtain tripled data from each rat compared to the traditional model. Three drugs, with different permeabilities, were utilized to evaluate the model: metoprolol, propranolol and cimetidine. Data was evaluated in comparison to the traditional method. Metoprolol and propranolol showed similar P(eff) values in the modified model in all segments. Segmental-dependent permeability was obtained for cimetidine, with lower P(eff) in the distal parts. Similar P(eff) values for all drugs were obtained in the traditional method, illustrating that the modified model is as accurate as the traditional, throughout a wide range of permeability characteristics, whether the permeability is constant or segment-dependent along the intestine. Three-fold higher statistical power to detect segmental-dependency was obtained in the modified approach, as each subject serves as his own control. In conclusion, the Triple SPIP model can reduce the number of animals utilized in segmental-dependent permeability research without compromising the quality of the data obtained.
Dahan
Arik
A
University of Michigan, College of Pharmacy, 428 Church Street, Ann Arbor, MI 48109-1065, USA.
West
Brady T
BT
Amidon
Gordon L
GL
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D002927:Cimetidine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D023421:Models, Animal; D010477:Perfusion / Q000379:methods*; D010539:Permeability; D011433:Propranolol / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
D002927:Cimetidine; D011433:Propranolol; D008790:Metoprolol