In vitro-in vivo extrapolation of zolpidem as a perpetrator of metabolic interactions involving CYP3A

• Published in: European journal of clinical pharmacology Vol. 66; no. 3; pp. 275 - 283
• Main Authors: Polasek, Thomas M, Sadagopal, Janani S, Elliot, David J, Miners, John O
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.03.2010; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Area Under Curve; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Computer Simulation; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors - pharmacology; Female; Humans; Liver - drug effects; Liver - enzymology; Male; Medical sciences; Metabolic Clearance Rate; Microsomes, Liver - enzymology; Midazolam - administration & dosage; Midazolam - pharmacokinetics; Models, Biological; Pharmacokinetics and Disposition; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pyridines - pharmacology; Recombinant Proteins - antagonists & inhibitors; Young Adult; Zolpidem; CYP3A; Zolpidem; Mechanism-based inactivation; Modelling and simulation; Drug-drug interactions; Midazolam; Cytochromes P450; In vitro-in vivo extrapolation; Agonist; Isozyme; Psychotropic; Benzodiazepine receptor; Inactivation; Imidazopyridine derivatives; Benzodiazepine derivatives; Drug interaction; Sedative; Mechanism of action; Human; Enzyme; Gabaergic agonist; Cytochrome P450; Hypnotic; Metabolism; In vitro; Extrapolation; In vivo; Simulation; Pharmacokinetics; Gabaergic receptor A
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-009-0760-2

Objectives To evaluate zolpidem as a mechanism-based inactivator of human CYP3A in vitro, and to assess its metabolic interaction potential with CYP3A drugs (in vitro-in vivo extrapolation; IV-IVE). Methods A co- vs. pre-incubation strategy was used to quantify time-dependent inhibition of human liver microsomal (HLM) and recombinant CYP3A4 (rCYP3A4) by zolpidem. Experiments involving a 10-fold dilution step were employed to determine the kinetic constants of inactivation (K I and k inact) and to assess the in vitro mechanism-based inactivation (MBI) criteria. Inactivation data were entered into the Simcyp population-based ADME simulator to predict the increase in the area under the plasma concentration-time curve (AUC) for orally administered midazolam. Results Consistent with MBI, the inhibitory potency of zolpidem toward CYP3A was increased following pre-incubation. In HLMs, the concentration required for half maximal inactivation (K I) was 122 µM and the maximal rate of inactivation (k inact) was 0.094 min⁻¹. In comparison, K I and k inact values with rCYP3A4 were 50 µM and 0.229 min⁻¹, respectively. Zolpidem fulfilled all other in vitro MBI criteria, including irreversible inhibition. The mean oral AUC for midazolam in healthy volunteers was predicted to increase 1.1- to 1.7-fold due to the inhibition of metabolic clearance by zolpidem. Elderly subjects were more sensitive to the interaction, with mean increases in midazolam AUC of 1.2- and 2.2-fold for HLM IV-IVE and rCYP3A4 IV-IVE, respectively. Conclusions Zolpidem is a relatively weak mechanism-based inactivator of human CYP3A in vitro. Zolpidem is unlikely to act as a significant perpetrator of metabolic interactions involving CYP3A.