Title page for ETD etd-04212010-084044


Type of Document Dissertation
Author Linardi, Renata Lehn
Author's Email Address rlinardi@vetmed.lsu.edu
URN etd-04212010-084044
Title Role of Gastrointestinal Multidrug Resistance (MDR1) Gene and P-glycoprotein (P-gp) in the Oral Absorption of Methadone in Horses
Degree Doctor of Philosophy (Ph.D.)
Department Veterinary Clinical Sciences
Advisory Committee
Advisor Name Title
Stokes, Ashley M. Committee Chair
Kousoulas, Konstantin G. Committee Co-Chair
Andrews, Frank M. Committee Member
Sehgal, Inder Committee Member
Ding, Huangen Dean's Representative
Keywords
  • Oral opioid absorption
  • Methadone
  • P-glycoprotein
  • MDR1 gene
Date of Defense 2010-03-26
Availability unrestricted
Abstract
Methadone is a mu-opioid receptor agonist which is a very effective analgesic used to treat moderate to severe acute and chronic pain in humans. Due to methadone’s minimal undesirable side-effects in people, we believed it could be of use in horses as an analgesic agent. As found with the majority of lipophilic drugs, absorption of methadone occurs primarily in the small intestine via transcellular transport and its absorption is regulated by P-glycoprotein. P-glycoprotein is a transmembrane transporter protein encoded by the multidrug resistance gene, which is constitutively expressed in the apical membrane of enterocytes of various species. This protein may impair the therapeutic efficacy of oral opioids including methadone, by decreasing absorption through the small intestinal mucosa and altering drug’s pharmacokinetics. The overall hypothesize was that the expression of P-glycoprotein in the equine small intestine affects absorption and bioavailability of methadone after oral administration to horses. In Vivo and in vitro studies presented here investigated the oral pharmacokinetics of methadone, expression of the multidrug resistance (MDR1) gene, and the role of intestinal P-glycoprotein on methadone flux or transport in equine jejunal mucosa. The contribution of this protein to in vivo absorption of this opioid drug after oral administration in horses is evaluated. Oral administration of methadone hydrochloride to healthy horses showed rapid absorption, reaching high serum concentrations without typical undesirable opioid-induced side effects. Drug absorption appears to be limited in the small intestine, supported by the observed low drug serum concentrations, low area under the drug serum concentration vs. time curve, and low drug bioavailability after intragastric administration. In addition, methadone was absorbed by oral mucosa and may be an important way that methadone gains entrance into equine plasma. Multidrug resistance (MDR1) gene expression was determined in several different tissues including those of the small intestine of horses. High MDR1 mRNA levels mainly in the duodenum and jejunum of horses may explain, at least in part, the limited intestinal absorption of methadone in vivo. P-glycoprotein, located in the apical membrane of epithelial intestinal cells of jejunum in horses impairs the flux of methadone across the intestinal mucosa and its drug efflux activity is minimized by verapamil HCl, a P-glycoprotein inhibitor. Therefore, these studies confirmed that the expression of P-glycoprotein in the equine small intestine affects absorption and bioavailability of methadone after oral administration to horses.
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