ABSTRACT
The effects of the cytochrome P450 (CYP)2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam were studied in 16 healthy male volunteers. The two mutated alleles (CYP2C19*2 and CYP2C19*3) causing absent CYP2C19 activity were identified by PCR-based restriction enzyme analysis. Five subjects had no mutated allele, five had one mutated allele, and six had two mutated alleles. Seven subjects were smokers, and nine were nonsmokers. The subjects received a single oral 4-mg dose of estazolam, and blood samplings and evaluation of psychomotor function were conducted up to 72 h after dosing. There was no significant difference among the groups with no, one, and two mutated alleles for the peak plasma concentration (145.2+/-36.5 vs. 142.1+/-33.6 vs. 113.2+/-29.7 ng/ml), area under the plasma concentration-time curve (0- infinity ) (4916.0+/-1276.4 vs. 4389.6+/-736.1 vs. 4047.3+/-613.8 ng x h/ml), apparent oral clearance (0.22+/-0.05 vs. 0.25+/-0.03 vs. 0.25+/-0.03 ml/min/kg), and elimination half-life (24.4+/-4.6 vs. 29.6+/-8.5 vs. 30.7+/-3.9 h). Similarly, none of the pharmacokinetic parameters was significantly different between the nonsmoker and smoker groups. Neither the number of mutated allele nor cigarette smoking affected the psychomotor function parameters significantly. The present study suggests that neither the CYP2C19 genotype nor cigarette smoking affects the single oral dose pharmacokinetics and pharmacodynamics of estazolam.
Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Estazolam/administration & dosage , Estazolam/pharmacokinetics , Mixed Function Oxygenases/genetics , Smoking/genetics , Smoking/metabolism , Administration, Oral , Adult , Analysis of Variance , Area Under Curve , Chi-Square Distribution , Cytochrome P-450 CYP2C19 , Estazolam/blood , Genotype , Humans , MaleABSTRACT
A patient with bilateral diminished visual acuity and blurred vision was given the diagnosis of psychogenic visual disturbance after extensive psychiatric and ophthalmological examinations. Single photon emission computed tomography with Tc-99m-ethylcysteinate dimer demonstrated remarkably reduced regional cerebral blood flow (rCBF) in the bilateral occipital lobes. More specifically, rCBF was reduced in the visual association areas, but not in the primary visual areas. These findings suggest that functional suppression of the visual association area is associated with the development of psychogenic visual disturbance.
Subject(s)
Occipital Lobe/blood supply , Occipital Lobe/physiopathology , Vision Disorders/physiopathology , Vision Disorders/psychology , Adult , Cerebrovascular Circulation/physiology , Electroencephalography , Humans , Magnetic Resonance Imaging , Male , Occipital Lobe/anatomy & histology , Tomography, Emission-Computed, Single-PhotonABSTRACT
A high-performance liquid chromatography (HPLC) assay was developed for the determination of estazolam in human plasma. Estazolam and alprazolam as an internal standard were detected by ultraviolet absorbance at 240 nm. Estazolam in plasma was extracted by a rapid and simple procedure based on cyanopropyl bonded-phase extraction. Chromatographic separation was achieved with a reversed-phase C8-5 column using a mobile phase of 0.5% potassium dihydrogenphosphate(pH 4.5)-acetonitrile (70:30, v/v). The determination of estazolam was possible in the concentration range of 1.0 - 200.0 ng/mL. The mean recovery of estazolam added to plasma was 96.1 +/- 1.5% with coefficients of variation of less than 5.5%. This method is applicable for accurately monitoring the plasma level of estazolam in healthy subjects participating in scientific research.
Subject(s)
Chromatography, High Pressure Liquid/methods , Estazolam/blood , Hypnotics and Sedatives/blood , Calibration , Estazolam/pharmacokinetics , Humans , Hypnotics and Sedatives/pharmacokinetics , Male , Reference Standards , Reference Values , Spectrophotometry, UltravioletABSTRACT
To examine the involvement of cytochrome P450 3A4 in the metabolism of estazolam, the effect of itraconazole, a potent inhibitor of this enzyme, on the single oral dose pharmacokinetics and pharmacodynamics of estazolam was studied in a double-blind randomized crossover manner. Ten healthy male volunteers received itraconazole 100 mg/day or placebo orally for 7 days, and on the 4th day they received a single oral 4-mg dose of estazolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale, and Stanford Sleepiness Scale were conducted up to 72 hours after estazolam dosing. There was no significant difference between the placebo and itraconazole phases for the peak plasma concentration, apparent oral clearance, and elimination half-life. Similarly, none of the psychomotor function parameters was significantly different between the two phases. The current study showed no significant effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam, suggesting that cytochrome P450 3A4 is not involved in the metabolism of estazolam to a major extent.
