Hylar L Friedman

Pharmacokinetics and pharmacodynamics of oral diazepam: Effect of dose, plasma concentration, and time

Eleven healthy subjects received single oral doses of placebo, 2 mg diazepam, 5 mg diazepam, and 10 mg diazepam in a randomized four‐way crossover study. Plasma diazepam levels, the Digit Symbol Substitution Test (DSST), and fraction of total electroencephalographic (EEG) amplitude falling in the sigma plus beta (13 to 31 Hz) frequency range were determined during the 12 hours after drug administration. Peak plasma diazepam concentration and area under the 12‐hour curve were proportional to dose; time of peak was independent of dose. Baseline percentage of EEG amplitude falling in the 13 to 31 Hz range averaged 15.7% and did not differ among the four trials. The percentage of EEG amplitude falling in the 13 to 31 Hz range did not change over baseline with placebo or 2 mg diazepam but was increased ¼ to 2½ hours after 5 mg diazepam, (maximum, +7.3%) and ¾ to 12 hours after 10 mg diazepam (maximum, + 15.2%). The increase in the percentage of EEG amplitude falling in the 13 to 31 Hz range was highly correlated with plasma diazepam concentration. DSST scores for placebo and 2 mg diazepam were nearly identical. DSST decrements with 5 and 10 mg diazepam paralleled and were correlated with the changes in the percentage of EEG amplitude falling in the 13 to 31 Hz range and with plasma diazepam levels. Thus the EEG analysis provides objective quantitation of benzodiazepine central nervous system effects, in turn reflecting plasma levels and other clinical measures.

Enhanced Bioavailability of Triazolam Following Sublingual Versus Oral Administration

The rate and extent of the absorption of triazolam following sublingual and oral administration were evaluated in this study. Eight healthy volunteers received triazolam 0.5 mg in a commercially available tablet, by sublingual and oral routes on two occasions in random sequence. Plasma triazolam concentrations during 24 hours after each dose were measured by electron‐capture gas‐liquid chromatography. The mean total area under the curve for sublingual administration was significantly larger than that following oral dosage (28.9 vs 22.6 ng‐hr/mL, P < .025). The peak plasma concentration after sublingual dosage was also higher than after oral administration (4.7 vs 3.9 ng/mL, P < .1). No significant differences between sublingual and oral administration were found for the elimination half‐life of triazolam (4.1 vs 3.7 hr) and the time of peak concentration (1.22 vs 1.25 hr) after dose. Thus, the bioavailability of triazolam after sublingual administration is increased by an average of 28% compared with oral administration of the same dose, possibly because first‐pass extraction is bypassed. Clinical effects of triazolam may likewise be enhanced by sublingual dosage.

Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol

Pharmacokinetics of the benzodiazepine bromazepam were evaluated in volunteer subjects who received single 6 mg oral doses followed by blood sampling during the next 48 hours. Age and gender effects were studied in 32 subjects, divided into young (aged 21 to 29 years) and elderly (aged 60 to 81 years) groups. Compared with young subjects, the elderly had significantly higher peak serum bromazepam concentrations (132 vs. 82 ng/ml), smaller volume of distribution (0.88 vs. 1.44 L/kg), lower oral clearance (0.41 vs. 0.76 ml/min/kg), and increased serum free fraction (34.8% vs. 28.8% unbound). However, gender had no significant influence on bromazepam kinetics. In 11 young female users of oral contraceptive steroids, compared with seven age‐ and weight‐matched control women not using oral contraceptives, no differences in bromazepam kinetics were observed. Coadministration of cimetidine (1.2 gm daily) significantly reduced bromazepam clearance (0.41 vs. 0.82 ml/min/kg) and prolonged elimination half‐life (29 vs. 23 hours). Propranolol (160 mg daily) significantly prolonged bromazepam half‐life (28 vs. 23 hours), but the reduction in clearance associated with propranolol (0.65 vs. 0.82 ml/min/kg) did not reach significance. Bromazepam has the pharmacokinetic characteristics of benzodiazepines with half‐life values between 20 and 30 hours. Consistent with its biotransformation pathway by hepatic microsomal oxidation, bromazepam clearance is significantly impaired in elderly individuals, by coadministration of cimetidine and possibly propranolol.

A large-sample study of diazepam pharmacokinetics.

Healthy male volunteers (n = 48) aged 18–44 years received a single 10-mg oral dose of diazepam. Plasma diazepam and desmethyldiazepam concentrations were measured at multiple points during the next 11 days. The distribution of peak plasma concentration (mean, 406 ng/ml) was not skewed and did not differ significantly from normal (Gaussian). However, the distributions of elimination half-life (44.2 h), elimination rate constant (0.0219/h), clearance (26.6 ml/min), and volume of distribution (83 L) all were significantly skewed and deviated significantly from normal. After logarithmic transformation, the distributions of elimination rate constant, elimination half-life, and volume of distribution were consistent with normal; however, this was not the case for time of peak plasma concentration. Thus, the pharmacokinetic characteristics of oral diazepam are highly variable even in a relatively homogeneous population. Parametric statistical testing procedures and pharmacokinetic forecasting schemes may be improved by more precise delineation of the underlying distributions for pharmacokinetic variables.

The pharmacokinetics and pharmacodynamics of sublingual and oral alprazolam in the post-prandial state

SummaryWe gave 12 healthy male volunteers 1 mg of alprazolam or placebo on three occasions after a standard breakfast in a double-blind, randomized, single-dose, three-way crossover study.The three trials were: (a) oral alprazolam and sublingual placebo; (b) oral placebo and sublingual alprazolam; (c) placebo by both routes.Plasma alprazolam concentrations during 24 h after each dose were measured by electron-capture gas-liquid chromatography.Peak plasma concentrations were reached later after sublingual than oral dosage (2.8 vs 1.8 h, P<0.01). Other kinetic variables were not significantly different: peak plasma concentration, 11.3 vs 12.0 ng·ml−1; elimination half-life, 12.5 vs 11.7 h; and total area under the plasma concentration versus time curve, 197 vs 186 h·ng·ml−1.Pharmacodynamic measures showed that sublingual and oral alprazolam both produced sedation, fatigue, impaired digit symbol substitution, slowing of reaction time, and impairment of the acquisition and recall of information. These changes were initially observed at 0.5 h after dosage and lasted up to 8 h.In general the two routes were significantly different from placebo but not from each other.

Biotransformation of Mestranol to Ethinyl Estradiol In Vitro: The Role of Cytochrome P‐450 2C9 and Metabolic Inhibitors

Mestranol, the estrogen component of some oral contraceptive formulations, must be demethylated to its active metabolite, 17α‐ethinyl estradiol, to produce estrogenic activity. To investigate the transformation of mestranol to ethinyl estradiol, an in vitro assay was used with human liver microsomes from four different donors. Incubation of a fixed concentration of mestranol (3 μmol/L) with varying concentrations of CYP inhibitors revealed strong inhibition of ethinyl estradiol formation by sulfaphenazole, a specific CYP2C9 inhibitor, with an average inhibitor concentration at one half of Emax (IC50) of 3.6 μmol/L (range, 1.8–8.3 μmol/L) and an average maximal inhibitory capacity (Emax) of 75% (range, 60–91%). Troleandomycin (a CYP3A3/4 inhibitor) and quinidine (a CYP2D6 inhibitor), however, produced no substantial inhibitory activity. α‐Naphthoflavone (a CYP1A1/2 inhibitor only at concentrations <2 μmol/L and a CYP2C9 inhibitor at higher concentrations) had a weak inhibitory effect on ethinyl estradiol formation (<20% decrease in mestranol demethylation activity). Of the three antifungal azoles tested, miconazole strongly inhibited mestranol demethylation, with an average IC50 of 1.5 μmol/L (range, 0.7–3.2 μmol/L) and an average Emax of 90% (range, 77–100%), whereas fluconazole displayed relatively weak inhibition only at the highest concentration of 50 μmol/L (mean reduction in demethylation activity was 29%). Itraconazole produced no meaningful inhibition. Strong inhibition of ethinyl estradiol formation by sulfaphenazole suggests a major contribution of CYP2C9 to this reaction.

Kinetics, brain uptake, and receptor binding characteristics of flurazepam and its metabolites

The benzodiazepine derivative flurazepam (FLZ) is widely used as a hypnotic, but the relative contributions of FLZ and its metabolites desalkylflurazepam (DA-FLZ), hydroxyethylflurazepam (ETOH-FLZ), and flurazepam aldehyde (CHO-FLZ) to overall clinical activity remain uncertain. A single 20 mg/kg dose of FLZ·HCl was administered to mice, with plasma and brain concentrations of FLZ and metabolites determined during 5 h after dosage. Brain and plasma concentrations of FLZ were maximal at 0.5 h after dosage, then declined rapidly in parallel, whereas those of DAFLZ were maximal at 2 h, then declined slowly. Concentrations of ETOH-FLZ, the most polar metabolite, were maximal at 0.5 h, and were undetectable after 3 h. Little CHO-FLZ was detected in either brain or plasma. A single 30-mg oral dose of FLZ·HCl was given to 18 human volunteers, with plasma levels determined over 9 days. FLZ was detected in plasma at low concentrations for no more than 3 h after dosage. ETOH-FLZ concentrations were higher and persisted for 8 h after dosage. CHO-FLZ reached intermediate peak levels and was present longer than FLZ or ETOH-FLZ. In contrast, DA-FLZ achieved the greatest peak concentrations, occurring at 10 h after dosage. Levels declined very slowly, with a mean half-life of 71.4 h, and were still detectable 9 days after FLZ dosage. Plasma free fractions (percent unbound) in mice were 40.3, 51.4, and 25.0% for FLZ, ETOH-FLZ and DA-FLZ, respectively; in humans, values were 17.2, 35.2, and 3.5%, respectively. Brain:free plasma ratios in mice for the three compounds were 8.17, 2.21 and 7.01, and were correlated with HPLC retention times, an index of lipophilicity (r=0.90), suggesting passive distribution from plasma to brain. In vitro specific binding affinities (Ki) in rat brain membranes for FLZ, ETOH-FLZ, DA-FLZ, and CHO-FLZ were 12.7, 16.2, 0.85, and 10.6 nM, respectively. Thus after a single 20 mg/kg dose of FLZ in mice, DA-FLZ brain concentrations greatly exceeded its Ki, while FLZ and ETOH-FLZ levels relative to their own Ki values are one or more orders of magnitude lower. Since brain:free plasma ratios and binding characteristics for benzodiazepines appear similar in rodents and humans, similar conclusions can be drawn for humans based on pharmacokinetic and protein binding data. Pharmacodynamic effects after a single dose of FLZ in mice and humans are largely attributable to DA-FLZ, consistent with behavioral studies comparing relative potencies of metabolites.

Evaluation of interaction between fluconazole and an oral contraceptive in healthy women.

OBJECTIVE To evaluate the potential pharmacokinetic interaction between 2 × 150 mg fluconazole administered once weekly and an oral contraceptive (OC) containing ethinyl estradiol and norethindrone. METHODS A placebo‐controlled, double‐masked, randomized, two‐way crossover study was used to investigate the pharmacokinetic interaction between 300 mg fluconazole once weekly and the OC Ortho Novum 7/7/7 (Ortho‐McNeil Pharmaceutical, Inc., Raritan, NJ) in 26 healthy women, 18–36 years old. In the first cycle (28 days), subjects received OC only. In the second cycle, subjects were assigned randomly to receive OC‐fluconazole or OC‐placebo. In the third cycle, subjects were crossed over to the opposite treatment. RESULTS Data for 21 subjects who completed the study were included in the pharmacokinetic analysis; data for all 26 subjects were included in the safety analysis (26 OC only; 24 OC‐fluconazole; 23 OC‐placebo). Treatment with OC‐fluconazole resulted in small but statistically significant increases in 0–24 hour area under the plasma concentration‐time curve (AUC0–24) for both ethinyl estradiol(mean 24%, 95% confidence interval [CI] 18%, 31%) and norethindrone (mean 13%, 95% CI 8%, 18%) as compared with treatment with OC‐placebo. Ethinyl estradiol maximum plasma concentration (Cmax) was slightly (mean 8%,95% CI 2%, 15%) though statistically significantly higher for OC‐fluconazole treatment as compared with OC‐placebo treatment. Norethindrone Cmax was not different (95% CI −6%, 11%) between the two treatment groups. No adverse events related to treatment were seen in the fluconazole treatment group. CONCLUSION The concomitant administration of 300 mg fluconazole once weekly, twice the recommended dose for vaginal candidiasis, to women using OCs results in a slight increase in OC concentrations. Therefore, it appears that there is no threat of contraceptive failure because of concomitant fluconazole administration.

Triazolam Kinetics: Interaction with Cimetidine, Propranolol, and the Combination

Nineteen healthy volunteers received a single 0.5‐mg oral dose of triazolam on four occasions under the following conditions: (1) triazolam alone; (2) triazolam with Cimetidine, 300 mg four times daily; (3) triazolam with propranolol, 40 mg four times daily; (4) triazolam with both Cimetidine and propranolol. Triazolam kinetics were determined from multiple plasma concentrations measured during 24 hours after each dose. Compared with control, peak plasma triazolam concentration (Cmax) was significantly increased by Cimetidine (5.4 versus 3.9 ng/mL), total area under the plasma concentration curve (AUC) increased (21.3 versus 16.1 ng/mL × hr), and oral clearance decreased (485 versus 668 mL/min). However triazolam half‐life was not increased. During propranolol alone, triazolam Cmax (4.1 ng/mL), AUC (14.3 ng/mL × hr), and clearance (759 mL/min) did not differ significantly from control, whereas kinetic variables for triazolam with Cimetidine plus propranolol were similar to those with Cimetidine alone. Plasma free fraction for triazolam (17 to 18% unbound) did not differ significantly among the four treatment conditions. Mean steady‐state plasma Cimetidine concentrations during trials 2 and 4 were similar (1.04 versus .98 μg/mL), whereas plasma propranolol was significantly higher during Cimetidine plus propranolol than with propranolol alone (47 versus 29 ng/ml, P < .001). Thus Cimetidine coadministration significantly inhibits triazolam clearance, causing increased triazolam AUC and Cmax, but without a prolongation in half‐life. Propranolol itself does not impair triazolam clearance, nor does propranolol potentiate the inhibitory effect of Cimetidine alone.

Kinetics and EEG Effects of Midazolam during and after 1‐Minute, 1‐Hour, and 3‐Hour Intravenous Infusions

The objective of this study was to evaluate the kinetics and dynamics of midazolam when administered by three different infusion schemes, using electroencephalography to measure pharmacodynamic effects. In a three‐way crossover study, 8 volunteers received midazolam (0.1 mg/kg) by constant‐rate intravenous infusion. The durations of midazolam infusions for the three trials were 1 minute, 1 hour, and 3 hours. Plasma midazolam concentrations and electroencephalographic (EEG) activity in the 13‐ to 30‐Hz range were monitored for 24 hours. Based on separate analysis of each subject‐trial, mean values for volume of distribution and distribution or elimination half‐life did not significantly vary. Central compartment volume and clearance differed among the three midazolam infusion trials; however, the magnitude of change was small. EEG activity in the 13‐ to 30‐Hz range significantly increased for all three midazolam infusion trials. Plots of midazolam plasma concentration versus pharmacodynamic EEG effect for the 1‐hour and 3‐hour infusion trials did not reveal evidence of either counterclockwise or clockwise hysteresis. Plots from the 1‐minute infusion trial demonstrated counterclockwise hysteresis, consistent with an equilibration effect‐site delay. This was incorporated into a kinetic‐dynamic model in which hypothetical effect‐site concentration was related to pharmacodynamic EEG effect via the sigmoid Emax model. Analysis of all three infusion trials together yielded the following mean estimates: maximum EEG effect, 16.3% over baseline; 50% maximum effective concentration, 31 ng/mL; and an apparent rate constant for drug disappearance from the effect compartment which approached infinity. Despite the delay in effect onset during the 1‐minute midazolam infusion, midazolam infusions in duration of up to 3 hours produce CNS sedation without evidence of tolerance.