The pharmacodynamic interaction between midazolam and its active metabolite alpha-OH-midazolam was investigated to evaluate whether estimates of relevant pharmacodynamic parameters are possible after administration of a mixture of the two. Rats were administered 10 mg/kg of midazolam, 15 mg/kg of alpha-OH-midazolam, or a combination of 3.6 mg/kg of midazolam and 35 mg/kg of alpha-OH-midazolam. Increase in the 11.5- to 30-Hz frequency band of the electroencephalogram was used as the pharmacodynamic endpoint. The pharmacodynamics of midazolam and alpha-OH-midazolam after combined administration were first analyzed according to an empirical and a competitive interaction model to evaluate each model's capability in retrieving the pharmacodynamic estimates of both compounds. Both models failed to accurately estimate the true pharmacodynamic estimates of midazolam and alpha-OH-midazolam. The pharmacodynamic interaction was subsequently analyzed according to a new mechanism-based model. This approach is based on classical receptor theory and allows estimation of the in vivo estimated receptor affinity and intrinsic in vivo drug efficacy. The relationship between stimulus and effect is characterized by a monotonically increasing function f, which is assumed to be identical for midazolam and alpha-OH-midazolam. The pharmacodynamic interaction is characterized by the classical equation for the competition between two substrates for a common receptor site. This mechanism-based interaction model was able to estimate the pharmacodynamic parameters of both midazolam and alpha-OH-midazolam with high accuracy. It is concluded that pharmacodynamic parameters of single drugs can be estimated after a combined administration when a mechanistically valid interaction model is applied.
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Drug Test Anal
July 2019
Toxicology and Pharmacology, KU Leuven, Leuven, Belgium.
In recent years, the use of skeletal tissue as an alternative matrix in forensic toxicology has received new interest. In cases where extreme decomposition has taken place, analysis of skeletal tissue is often the only option left. In this article, a fully validated method is presented and the distribution of clomipramine, citalopram, midazolam, and metabolites after chronically administration is examined within skeletal tissue.
View Article and Find Full Text PDFJ Mass Spectrom
June 2006
National Public Health Institute, Drug Research Unit, Mannerheimintie 166, 00300 Helsinki, Finland.
Fast gas chromatography/negative-ion chemical ionization mass spectrometric (GC/NICI-MS) assay combined with rapid and nonlaborious sample preparation is presented for the simultaneous determination of benzodiazepines and alpha-hydroxy metabolites, zaleplon and zopiclone in whole blood. The compounds were extracted from 100 microl of whole blood by simultaneous multitube, microscale liquid-liquid extraction (LLE) and derivatized by N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (MTBSTFA), without the need for the time-consuming concentration stage. In the analytical separation, various parameters of fast GC/NICI-MS were applied, e.
View Article and Find Full Text PDFJ Pharmacol Exp Ther
May 1999
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden, The Netherlands.
The pharmacodynamic interaction between midazolam and its active metabolite alpha-OH-midazolam was investigated to evaluate whether estimates of relevant pharmacodynamic parameters are possible after administration of a mixture of the two. Rats were administered 10 mg/kg of midazolam, 15 mg/kg of alpha-OH-midazolam, or a combination of 3.6 mg/kg of midazolam and 35 mg/kg of alpha-OH-midazolam.
View Article and Find Full Text PDFEur J Clin Pharmacol
January 1997
Department of Pharmacology and Toxicology, University of Helsinki, Finland.
Objectives: Since grapefruit juice (Gra) inhibits hepatic P450 (CYP3A4), we studied its potential to enhance the effects of midazolam (Mid) and triazolam (Trz), which are metabolized by the CYP3A4 isoenzyme.
Methods: In Study I parallel groups of healthy students were given orally Mid 10 mg with water or grapefruit juice (GraMid), two placebo groups receiving water or Gra. The effects of Mid were measured by psychomotor tests and by self-rating on visual analogue scales before and 30 and 90 min after intake.
Int J Clin Pharmacol Ther
September 1995
Department of Pharmacology and Toxicology, University of Helsinki, Finland.
Fluconazole, an azole antifungal agent, moderately inhibits the CYP3A-mediated metabolism of midazolam in vitro. We therefore studied whether such an interaction takes place in vivo following oral administration of these drugs, given as relevant double blinded doses in capsule form. In study I parallel groups of healthy subjects received oral midazolam 10 mg (MID 10) or 15 mg (MID 15), placebo, or MID 10 mg + 150 mg fluconazole (FLU) given 2 h earlier.
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