Probe of CYP3A by a single-point blood measurement after oral administration of midazolam in healthy elderly volunteers.
BACKGROUND
Midazolam (MDZ) is used as an assessment of human cytochrome P450 3A (CYP3A) activity. A single blood measurement is used as a marker of its activity based on an observed correlation between MDZ clearance and the 1'-hydroxymidazolam (1'-OH-MDZ): MDZ plasma ratio is assessed at 0.5 h followig the intake of a single 7.5 mg oral dose of MDZ in healthy young volunteers. In addition, a 4-h plasma MDZ measurement has been found to be an excellent predictor of AUC and CYP3A activity.


OBJECTIVE
The main aim of this study was to define a single-point blood sampling in healthy elderly volunteers. The secondary objective was to investigate the pharmacological effects of a low oral dose of MDZ (5 mg) and its potential psychometric changes.


METHODS
Eight healthy elderly Caucasian volunteers participated in a single-dose, open-label, non-comparative study. Each subject received a single 5 mg oral dose of MDZ. Plasma concentrations of MDZ and its major metabolite, 1'-OH-MDZ, were assayed over 12 h. Secondary assessments of critical flicker fusion (CFF), body sway and mini-mental state examination were also carried out during the 12-h post-administration period.


RESULTS
A moderate correlation was observed between MDZ clearance and the 1'-OH-MDZ: MDZ plasma concentration ratio at 9 h post-dosing (Rho=0.81; p=0.04), but an even better correlation (Rho=0.99; p<0.009) was found between MDZ AUC and MDZ plasma concentration at 6 h post-dosing, with the latter value corresponding approximately to the average mean residence time (MRT) determined in our trial. This study was well-tolerated despite a significant transitory decrease (relative to baseline) in cortical arousal at 1 h post-dosing, as assessed by CFF, and a non-significant decrease (relative to baseline) in balance and vigilance also measured at 1 h and assessed on body sway, compared to baseline values.


CONCLUSIONS
Despite the small sample size, based on the results of healthy, elderly volunteers, a single MDZ plasma measurement taken at 6 h post-oral administration may represent an accurate marker of CYP3A phenotype. This single-time-point method could be used safely for predicting drug-drug or diet interactions and identifying individuals with genetic polymorphism that affect CYP3A activity.
Krupka
Emmanuel
E
Department of Clinical Pharmacology, University Hospital, 2 rue de la Miletrie, 86021 Poitiers, France.
Venisse
Nicolas
N
Lafay
Claire
C
Gendre
David
D
Diquet
Bertrand
B
Bouquet
Serge
S
Perault
Marie-Christine
MC
D000368:Aged; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects
D006993:Hypnotics and Sedatives; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam