title: Increased drug delivery to the brain by P-glycoprotein inhibition.
abstract: BACKGROUND
  Although the antidiarrheal loperamide is a potent opiate, it does not produce opioid central nervous system effects at usual doses in patients. On the basis of in vitro studies demonstrating that loperamide is a substrate for the adenosine triphosphate-dependent efflux membrane transporter P-glycoprotein, we postulated that inhibition of P-glycoprotein with quinidine would increase entry of loperamide into the central nervous system with resultant respiratory depression.
  
  
  METHODS
  To test this hypothesis, a 16-mg dose of loperamide was administered to eight healthy male volunteers in the presence of either 600 mg quinidine, a known inhibitor of P-glycoprotein, or placebo. Central nervous system effects were measured by evaluation of the respiratory response to carbon dioxide rebreathing as a measure of opiate-induced respiratory depression.
  
  
  RESULTS
  Loperamide produced no respiratory depression when administered alone, but respiratory depression occurred when loperamide (16 mg) was given with quinidine at a dose of 600 mg (P < .001). These changes were not explained by increased plasma loperamide concentrations.
  
  
  CONCLUSIONS
  This study therefore demonstrates first the potential for important drug interactions to occur by a new mechanism, namely, inhibition of P-glycoprotein, and second that the lack of respiratory depression produced by loperamide, which allows it to be safely used therapeutically, can be reversed by a drug causing P-glycoprotein inhibition, resulting in serious toxic and abuse potential.
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Sadeque
authors.forename: C
authors.initials: C
authors.lastname: Wandel
authors.forename: H
authors.initials: H
authors.lastname: He
authors.forename: S
authors.initials: S
authors.lastname: Shah
authors.forename: A J
authors.initials: AJ
authors.lastname: Wood
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D000930:Antidiarrheals / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002245:Carbon Dioxide / Q000494:pharmacology; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D008139:Loperamide / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D011802:Quinidine / Q000494:pharmacology*; D012119:Respiration / Q000187:drug effects*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000317:Adrenergic alpha-Antagonists; D000930:Antidiarrheals; D002245:Carbon Dioxide; D008139:Loperamide; D011802:Quinidine