Ann Locniskar

Effect of Age, Gender, and Obesity on Midazolam Kinetics

&NA; The effects of age, sex, and obesity on the kinetics of single intravenous (iv) and oral doses of midazolam were evaluated in healthy volunteers who received 2.5‐5 mg of iv midazolam on one occasion and 5‐10 mg orally on another. Kinetics were determined from multiple plasma midazolam concentrations measured during 24 h after dosage. Midazolam elimination half‐life (t1/2) after iv dosage was significantly prolonged in elderly (aged 60‐74 yr) versus young (24‐33 yr) males (5.6 vs. 2.1 hours, P < 0.01) and total clearance was significantly reduced (4.4 vs. 7.8 ml • min‐1 • kg‐1, P < 0.01), leading to increased systemic availability of the oral dose (50% vs. 41%, P < 0.05). However total volume of distribution calculated by the area method (Vd) (1.6 vs. 1.3 1/kg) and protein binding (3.5 vs. 3.4% unbound) did not differ between groups. Among women there were no significant differences between elderly (64‐79 yr) and young (23‐37 yr) volunteers in t1/2 (4.0 vs. 2.6 h), clearance (7.5 vs. 9.4 ml • min‐1 • kg‐1), Vd (2.1 vs. 2.0 1/kg), protein binding (3.7% vs. 3.7% unbound), or oral bioavailability (38% vs. 36%). In obese volunteers (mean weight 117 kg; 173% of ideal weight) versus control subjects of normal weight (66 kg, 95% of ideal weight) matched for age, sex, and smoking habits, midazolam Vd was increased significantly (311 vs. 114 1, P < 0.001). Vd was greater in the obese subjects even after correction for total weight (2.7 vs. 1.7 1/kg, P < 0.001), indicating disproportionate distribution of midazolam into adipose weight. Since clearance was not different between groups (472 vs. 530 ml/ min), the prolonged t1/2 in obese subjects (8.4 vs. 2.7, P < 0.001) was due to the increased Vd. The clinical consequences of age‐ and obesity‐related changes in midazolam kinetics will depend on the circumstances of administration.

Lorazepam kinetics in the elderly

Lorazepam is a 3‐hydroxy‐1,4‐benzodiazepine derivative biotransformed by glucuronide conjugation, followed by urinary excretion of the glucuronide metabolite. The kinetic properties of single 1.5‐ to 3.0‐mg doses of intravenous lorazepam were assessed in 15 healthy elderly subjects, 60 to 84 yr of age, and in 15 healthy young subjects, 19 to 38 yr of age. Volumes of distribution for lorazepam in the elderly group (mean, 0.99 1/kg), were slightly but significantly smaller than in the young group (1.11 1/kg), suggesting less extensive drug distribution in the elderly. Values of elimination half‐life (t½β) in the elderly (15.9 hr) did not differ significantly from those in the young group (14.1 hr), but total clearance in the elderly (0.77 ml/min/kg) was 22% less (p < 0.05) than in the young subjects (0.99 ml/min/kg). Age differences in lorazepam clearance were partly explained by more frequent cigarette smoking in the young subjects. Gender had no apparent relationship to kinetics. The rate and completeness of absorption of intramuscular (IM) and oral lorazepam was assessed in 10 of the elderly subjects. Deltoid 1M injection and oral administration of tablets in the fasting state led to rapid absorption of lorazepam into the systemic circulation. Peak plasma lorazepam concentrations were always reached within 2.5 hr, and values of absorption half‐life (t½α) did not exceed 45 min. Absorption of IM and oral lorazepam was 80% to 100% complete. Thus, the aging process is associated with small changes in the kinetics of lorazepam. IM and oral administration of lorazepam in elderly persons, as in the case of young individuals, leads to rapid and nearly complete absorption into the systemic circulation.

Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo

Eleven healthy volunteers received a single intravenous dose of diazepam (0.15 mg/kg), midazolam (0.1 mg/kg), and placebo by 1‐minute infusion in a double‐blind, three‐way crossover study. Plasma concentrations were measured during 24 hours after dosage, and the electroencephalographic (EEG) power spectrum was simultaneously computed by fast‐Fourier transform to determine the percentage of total EEG amplitude occurring in the 13 to 30 Hz range. Both diazepam and midazolam had large volumes of distribution (1.2 and 2.3 L/kg, respectively), but diazepams half‐life was considerably longer (33 versus 2.8 hours) and its metabolic clearance lower (0.5 versus 11.0 ml/min kg) than those of midazolam. EEG changes were maximal at the end of the diazepam infusion and 5 to 10 minutes after midazolam infusion. Percent 13 to 30 Hz activity remained significantly above baseline until 5 hours for diazepam but only until 2 hours for midazolam. For both drugs, EEG effects were indistinguishable from baseline by 6 to 8 hours, suggesting that distribution contributes importantly to terminating pharmacodynamic action. The relationship of EEG change to plasma drug concentration indicated an apparent EC50 value of 269 ng/ml for diazepam as opposed to 35 ng/ml for midazolam. However, Emax values were similar for both drugs (+19.4% and + 21.3%, respectively).

Automated Gas Chromatography for Studies of Midazolam Pharmacokinetics

Plasma midazolam concentrations following single therapeutic doses can be quantitated using electron-capture gas-liquid chromatography. After addition of a benzodiazepine analogue as an internal standard, samples are extracted with benzeneisoamyl alcohol (98.5:1.5). The organic extract is evaporated to dryness, reconstituted, and chromatographed on an SP-2250 liquid phase. The automatic sampler allows up to 100 chromatographic analyses per 24-h period. The sensitivity limits are 2-3 ng of midazolam per ml of plasma, and the variation of identical samples is 7 per cent or less. The method was used in a study of six females who received single intravenous doses of midazolam for purposes of anesthetic induction prior to minor gynecologic procedures. Mean (+/- SE) kinetic variables for midazolam were: volume of central compartment, 0.37 (+/ 0.06 l/kg; total volume of distribution, 1.72 (+/- 0.05) l/kg: initial distribution half-life, 7.2 (+/- 1.6) min; elimination half-life, 2.5 (+/- 0.2) h; total clearance, 8.1 (+/- 0.52) ml.min-1.kg-1.

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.

Age, sex, and nitrazepam kinetics: Relation to antipyrine disposition

Forty healthy men and women 19 to 80 years old received a single 10 mg oral dose of the 7‐nitro benzodiazepine nitrazepam. Nitrazepam plasma concentrations were measured during the next 72 hours. Among men, the elderly had a larger volume of distribution (Varea) than did younger subjects (1.96 vs. 1.63 L/kg; P < 0.05); because clearance did not change with age (0.84 vs. 0.95 ml/min/kg), the prolonged t½ in elderly men (28 vs. 20 hours; P < 0.01) was a result of the larger Varea. Elderly and young women did not differ in nitrazepam Varea (2.58 vs. 2.55 L/kg), t½ (26 vs. 27 hours), or total clearance (1.19 vs. 1.09 ml/min/kg). The nitrazepam free fraction in plasma (18% to 19% unbound) was not related to age or sex. Among 18 subjects who also received antipyrine, the clearance of nitrazepam and antipyrine were not correlated (r = 0.23). Thus age minimally influences nitrazepam clearance (accomplished mainly by nitroreduction), which in turn is not significantly related to antipyrine oxidizing capacity.

Interaction of Diazepam With Famotidine and Cimetidine, Two H2-Receptor Antagonists

Famotidine is currently under investigation as an H2‐receptor antagonist. Eleven healthy male volunteers received a single 10 mg intravenous dose of diazepam on three occasions: once during coadministration of famotidine 40 mg bid, once during coadministration of cimetidine 300 mg qid, and once without other drug treatment (control). Multiple blood samples were drawn during the seven days after each diazepam dose. Diazepam and desmethyldiazepam plasma concentrations were measured by electron capture gas chromatography. There were no significant differences among the three treatment conditions in diazepam central compartment volume or total volume of distribution. During the cimetidine as compared with the control treatment, diazepam elimination half‐life was significantly increased (72 vs 55 hr, P < .05), total area under the curve (AUC) increased (11.8 vs 9.8 hr‐μg/mL, P < .05), and total clearance reduced (0.20 vs 0.28 mL/min/kg, P < .05). Seven‐day AUC for desmethyldiazepam also increased (4.6 vs 3.8 hr‐μg/mL, P < .05). However, there were no significant differences between famotidine and control treatment conditions in diazepam elimination half‐life (53 vs 55 hr), total AUC (9.5 vs 9.8 hr‐μg/mL), or total clearance (0.28 vs 0.28 mL/min/kg) or in seven‐day AUC for desmethyldiazepam (3.9 vs 3.8 hr‐μg/mL). Thus, therapeutic doses of cimetidine significantly impair the clearance of diazepam and desmethyldiazepam. Therapeutic doses of famotidine do not impair diazepam and desmethyldiazepam kinetics, suggesting that there is no significant kinetic interaction when diazepam and famotidine are administered concurrently in clinical practice.

Alprazolam Pharmacokinetics in Women on Low‐Dose Oral Contraceptives

Sixteen women chronically using low‐dose estrogen‐containing oral contraceptive steroids (OCs) and 23 drug‐free control women received a single 1‐mg oral dose of alprazolam. Multiple plasma samples drawn during 48 hours after the dose were analyzed by electron‐capture gas‐liquid chromatography. There were no significant differences between controls and oral contraceptive users in alprazolam volume of distribution (1.27 versus 1.39 L/kg), elimination half‐life (11.9 versus 12.3 hours), total clearance (1.36 versus 1.39 mL/min/kg), or total area under the plasma concentration versus time curve (227 versus 243 ng/mL × hr). Alprazolam free fraction in plasma was slightly but significantly greater in the oral contraceptive group as opposed to the control group (28.4 versus 27.0% unbound), respectively. However, comparison of free clearance between groups revealed no significant difference (4.61 versus 4.89 mL/min/kg, respectively). Thus, low‐dose estrogen‐containing oral contraceptives do not significantly influence the metabolic clearance of alprazolam.

Pharmacokinetics of Benzodiazepine Hypnotics

Three benzodiazepine derivatives are currently indicated specifically for the treatment of insomnia in the United States. Flurazepam is biotransformed to at least two rapidly appearing and rapidly eliminated intermediate metabolites which probably contribute to sleep induction. The final metabolite, desalkylflurazepam, appears slowly, but has a long half-life ranging from 40 to 150 h. This metabolite accumulates extensively during multiple dosage. Temazepam is a slowly absorbed drug and has an intermediate half-life in the range of 10-20 h. Triazolam has an intermediate absorption rate, but is rapidly eliminated (half-life 1.5-5 h) making it essentially non-accumulating. Understanding of the pharmacokinetics of benzodiazepine hypnotics can contribute to understanding of their clinical properties.