title: Evaluation of the pharmacokinetic interaction of midazolam with ursodeoxycholic acid, ketoconazole and dexamethasone by brain benzodiazepine receptor occupancy.
abstract: OBJECTIVE
  To clarify whether alterations in midazolam pharmacokinetics resulting from changes in cytochrome P450 3A (CYP3A) activity lead to changes in its pharmacodynamic effects, benzodiazepine receptor occupancy was measured in the brain of rats after oral administration of midazolam.
  
  
  METHODS
  Receptor occupancy was measured by radioligand binding assay in rats pretreated with ursodeoxycholic acid (UDCA), ketoconazole and dexamethasone, and the plasma concentration of midazolam was simultaneously determined.
  
  
  RESULTS
  There was a significant increase in the apparent dissociation constant and decrease in the maximum number of binding sites for specific [(3) H]flunitrazepam binding after oral administration of midazolam at pharmacologically relevant doses, suggesting that midazolam binds significantly to brain benzodiazepine receptors. Pretreatment with UDCA significantly enhanced the binding. This correlated well with significant enhancement by UDCA of the plasma midazolam concentration. The brain benzodiazepine receptor binding of oral midazolam was significantly enhanced by pretreatment with ketoconazole, a potent inhibitor of CYP3A, whereas it was significantly reduced by treatment with dexamethasone, an inducer of this enzyme. These effects paralleled changes in the plasma concentration of midazolam.
  
  
  CONCLUSIONS
  The results indicate that pharmacokinetic changes such as altered CYP3A activity significantly influence the pharmacodynamic effect of midazolam by affecting occupancy of benzodiazepine receptors in the brain. They also suggest in-vivo or ex-vivo time-dependent measurements of receptor occupancy by radioligand binding assay to be a tool for elucidating the pharmacokinetic interaction of benzodiazepines with other agents in pre-clinical and clinical evaluations.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, Global Center of Excellence (COE), Practical Pharmacy and Clinical Pharmaceutics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Shingen
authors.initials: S
authors.lastname: Misaka
authors.forename: Souhei
authors.initials: S
authors.lastname: Kurosawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Uchida
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshida
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kato
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kagawa
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018757:GABA Modulators / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013997:Time Factors; D014580:Ursodeoxycholic Acid / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018757:GABA Modulators; D011963:Receptors, GABA-A; D014580:Ursodeoxycholic Acid; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D007654:Ketoconazole