Back to Search
Start Over
Evaluation of the pharmacokinetic interaction of midazolam with ursodeoxycholic acid, ketoconazole and dexamethasone by brain benzodiazepine receptor occupancy.
- Source :
-
The Journal of pharmacy and pharmacology [J Pharm Pharmacol] 2011 Jan; Vol. 63 (1), pp. 58-64. Date of Electronic Publication: 2010 Nov 16. - Publication Year :
- 2011
-
Abstract
- Objectives: 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.<br />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.<br />Key Findings: 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.<br />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.<br /> (© 2010 The Authors. JPP © 2010 Royal Pharmaceutical Society.)
- Subjects :
- Administration, Oral
Animals
Brain metabolism
Cytochrome P-450 CYP3A metabolism
Dexamethasone pharmacology
Drug Interactions
Enzyme Induction drug effects
Enzyme Inhibitors pharmacology
GABA Modulators metabolism
GABA Modulators pharmacology
Ketoconazole pharmacology
Male
Midazolam metabolism
Midazolam pharmacology
Protein Binding
Radioligand Assay
Rats
Rats, Sprague-Dawley
Time Factors
Ursodeoxycholic Acid pharmacology
Cytochrome P-450 CYP3A drug effects
GABA Modulators pharmacokinetics
Midazolam pharmacokinetics
Receptors, GABA-A metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2042-7158
- Volume :
- 63
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 21155816
- Full Text :
- https://doi.org/10.1111/j.2042-7158.2010.01176.x