The effect of P-Glycoprotein on methadone hydrochloride flux in equine intestinal mucosa

• Published in: Journal of veterinary pharmacology and therapeutics 2013-02, Vol.36 (1), p.43-50
• Main Authors: LINARDI, R. L., STOKES, A. M., ANDREWS, F. M.
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - pharmacology; Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - pharmacology; Horses; Intestinal Absorption - drug effects; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Jejunum - drug effects; Jejunum - metabolism; Methadone - pharmacokinetics; Rhodamine 123 - pharmacology; Verapamil - pharmacology
• ISSN: 0140-7783; 1365-2885
• DOI: 10.1111/j.1365-2885.2012.01390.x

Linardi, R. L., Stokes, A. M., Andrews, F. M. The effect of P‐Glycoprotein on methadone hydrochloride flux in equine intestinal mucosa. J. vet. Pharmacol. Therap. 36, 43–50. Methadone is an effective analgesic opioid that may have a place for the treatment of pain in horses. However, its absorption seems to be impaired by the presence of a transmembrane protein, P‐glycoprotein, present in different tissues including the small intestine in other species. This study aims to determine the effect of the P‐glycoprotein on methadone flux in the equine intestinal mucosa, as an indicator of in vivo drug absorption. Jejunum tissues from five horses were placed into the Ussing chambers and exposed to methadone solution in the presence or absence of Rhodamine 123 or verapamil. Electrical measurements demonstrated tissue viability for 120 min, and the flux of methadone across the jejunal membrane (mucosal to submucosal direction) was calculated based on the relative drug concentration measured by ELISA. The flux of methadone was significantly higher only in the presence of verapamil. P‐glycoprotein was immunolocalized in the apical membrane of the jejunal epithelial cells (enterocytes), mainly located in the tip of the villi compared to cells of the crypts. P‐glycoprotein is present in the equine jejunum and may possibly mediate the intestinal transport of methadone. This study suggests that P‐glycoprotein may play a role in the poor intestinal absorption of methadone in vivo.