Jerold S. Harmatz

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.

Diazepam disposition determinants.

Factors influencing diazepam kinetics were assessed in 4 equal groups (n = 11) of young male and female (aged 21 to 37 yr) and elderly male and female (aged 61 to 84 yr) subjects, all of whom were healthy. In all 44, plasma diazepam concentrations were determined by electron‐capture gas‐liquid chromatography in multiple samples drawn for as long as 9 days after a single 5‐ to 10‐mg intravenous dose. Based upon total (bound + free) diazepam concentrations, volume of distribution (Vd) ranged from 0.7 to 4.7 l/kg, and became larger both with increasing age and with female sex. Clearances of total (bound + free) diazepam in young and elderly females were nearly identical (0.51 and 0.48 ml/min/kg), but clearance was higher in young than elderly males (0.39 and 0.24 ml/min/kg, p < 0.01). The unbound fraction of diazepam in plasma (range, 0.9% to 2.7%) did not depend on sex, but was greater in the elderly than in the young. In part this related to lower plasma albumin concentrations in the elderly. After correction of kinetic data for individual differences in free fraction, Vd was larger in the females than in the males, but the effect of age was small. Clearance of unbound diazepam (intrinsic clearance) tended to be higher in the females than in the males of both age groups, and was higher in the young than in the elderly of both sexes (male: 29.9 and 14.9 ml/min/kg, p < 0.005; female: 43.6 and 28.0 ml/min/kg, p < 0.05). Smoking was associated with higher clearance values, particularly among young subjects.

Dose‐Dependent Pharmacokinetics and Psychomotor Effects of Caffeine in Humans

Twelve healthy volunteers received oral placebo, 250 mg of caffeine, and 500 mg of caffeine in a randomized, double‐blind, single‐dose crossover study. Caffeine kinetics were nonlinear, with clearance significantly reduced and elimination half‐life prolonged at the 500‐mg compared to the 250‐mg dose. The lower dose of caffeine produced more favorable subjective effects than the higher dose (elation, peacefulness, pleasantness), whereas unpleasant effects (tension, nervousness, anxiety, excitement, irritability, nausea, palpitations, restlessness) following the 500‐mg dose exceeded those of the 250‐mg dose. The lower dose of caffeine enhanced performance on the digit symbol substitution test and a tapping speed test compared to placebo; high‐dose caffeine produced less performance enhancement than the lower dose. The plasma concentration versus response relationship revealed concentration‐dependent increases in anxiety and improvements in cognitive and motor performance at low to intermediate concentrations. Both caffeine doses reduced electroencephalographic amplitude over the 4 Hz to 30 Hz spectrum, as well as in the alpha (8–11 Hz) and beta (12–30 Hz) ranges; however, effects were not dose‐dependent. While favorable subjective and performance‐enhancing stimulant effects occur at low to intermediate caffeine doses, the unfavorable subjective and somatic effects, as well as performance disruption, from high doses of caffeine may intrinsically limit the doses of caffeine used in the general population.

A double-blind placebo controlled study of desipramine in the treatment of ADD. I: Efficacy

The tricyclic antidepressant drug desipramine (DMI) was evaluated in the treatment of young patients with attention deficit disorder with hyperactivity (ADDH) in an unselected sample of 62 clinically referred patients, 43 (69%) of whom previously responded poorly to psychostimulant treatment. The 42 children and 20 adolescents were assigned randomly to receive DMI (N = 31) or placebo (N = 31) for up to 6 weeks in a parallel groups, double-blind study. Clinically and statistically significant differences in behavioral improvement were found for DMI over placebo, at an average (+/- SEM) maximal daily dose of 4.6 +/- 0.2 mg/kg; 68% of DMI-treated patients were considered very much or much improved, compared with only 10% of placebo patients (p less than 0.001). DMI was well tolerated, even at the relatively high doses used. These findings suggest that DMI can be an effective treatment in the management of pediatric patients with ADDH, including patients who failed to respond to stimulants.

Protease Inhibitors as Inhibitors of Human Cytochromes P450: High Risk Associated with Ritonavir

Four protease inhibitor antiviral agents (ritonavir, indinavir, nelfinavir, saquinavir) were evaluated as in vitro inhibitors of the activity of six human cytochromes using an in vitro model based on human liver microsomes. Ritonavir was a highly potent inhibitor of P450‐3A activity (triazolam hydroxylation), having inhibitory potency slightly less than ketoconazole. Indinavir was also a potent 3A inhibitor, while nelfinavir and saquinavir were less potent. Ritonavir had high inhibition potency against cytochrome P450‐2C9 (tolbutamide hydroxylation), −2C19 (S‐mephenytoin hydroxylation), and −2D6 (dextromethorphan O‐demethylation and desipramine hydroxylation), while the other protease inhibitors had one or more orders of magnitude lower inhibitory activity against these reactions. None of the protease inhibitors had important inhibitory potency against P450‐1A2 (phenacetin O‐deethylation) or −2E1 (chlorzoxazone hydroxylation). Thus, among available protease inhibitors, ritonavir carries the highest risk of incurring drug interactions due to inhibition of cytochrome P450 activity.

Midazolam Hydroxylation by Human Liver Microsomes In Vitro: Inhibition by Fluoxetine, Norfluoxetine, and by Azole Antifungal Agents

Biotransformation of the imidazobenzodiazepine midazolam to its α‐hydroxy and 4‐hydroxy metabolites was studied in vitro using human liver microsomal preparations. Formation of α‐hydroxy‐midazolam was a high‐affinity (Km = 3.3 μmol/L) Michaelis‐Menten process coupled with substrate inhibition at high concentrations of midazolam. Formation of 4‐hydroxy‐midazolam had much lower apparent affinity (57 μmol/L), with minimal evidence of substrate inhibition. Based on comparison of Vmax/Km ratios for the two pathways, α‐hydroxy‐midazolam formation was estimated to account for 95% of net intrinsic clearance. Three azole antifungal agents were inhibitors of midazolam metabolism in vitro, with inhibition being largely consistent with a competitive mechanism. Mean competitive inhibition constants (Ki) versus α‐hydroxy‐midazolam formation were 0.0037 μmol/L for ketoconazole, 0.27 μmol/L for itraconazole, and 1.27 μmol/L for fluconazole. An in vitro‐in vivo scaling model predicted inhibition of oral midazolam clearance due to coadministration of ketoconazole or itraconazole; the predicted inhibition was consistent with observed interactions in clinical pharmacokinetic studies. The selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine and its principal metabolite, norfluoxetine, also were inhibitors of both pathways of midazolam biotransformation, with norfluoxetine being a much more potent inhibitor than was fluoxetine itself. This finding is consistent with results of other in vitro studies and of clinical studies, indicating that fluoxetine, largely via its metabolite norfluoxetine, may impair clearance of P450‐3A substrates.

Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part II).

SummaryPart I of this article, which appeared in the previous issue of the Journal, discussed the scope of and scientific basis for special pharmacokinetic studies of anxiolytic and hypnotic drugs in the elderly, and examined the methodology and results of such studies and the prediction of pharmacokinetic changes. In Part II the authors continue their review, focusing on age-related pharmacodynamic changes in the effects of these drugs, the attempts to correlate pharmacokinetic with pharmacodynamic findings, and the clinical applications of these data.

Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine : comparison with other selective serotonin reuptake inhibitor antidepressants

In vitro preparations of human liver microsomes were used to study the inhibiting effects of two selective serotonin reuptake inhibitor (SSRI) antidepressants, paroxetine and fluvoxamine, on metabolism via hydroxylation of alprazolam and of desipramine. These reactions are mediated by Cytochromes P450-3A4 and P450-2D6, respectively. Paroxetine was a highly potent inhibitor of desipramine hydroxylation; the inhibition constant (Ki) value of 2.0 microM indicated greater inhibiting potency than fluoxetine or norfluoxetine. The in vitro data predicted in vivo impairment of desipramine clearance by coadministration of paroxetine which was in the same range as observed in a clinical study. Fluvoxamine, by contrast, was a much weaker inhibitor of desipramine hydroxylation, having a Ki value (16.6 microM) similar to those of sertraline and desmethylsertraline. For hydroxylation of alprazolam, paroxetine was a relatively weak inhibitor, approximately comparable to fluoxetine, whereas fluvoxamine showed inhibiting capacity similar to that of norfluoxetine. The in vitro data predicted the degree of impairment of alprazolam clearance observed in vitro model can therefore provide clinically relevant data on prediction of potential drug interactions with SSRIs.

Clinical Pharmacokinetics of Anxiolytics and Hypnotics in the Elderly

SummaryAnxiolytic and hypnotic drugs are extensively prescribed for elderly individuals throughout Western society. Old age may be associated with an altered clinical response to this class of compounds, and there is a considerable ethical and economic stake in understanding these changes so that therapy may be approached with a maximum likelihood of therapeutic benefit and a minimum risk of side effects.Old age may lead to altered pharmacokinetics of sedative-anxiolytic drugs, causing higher plasma concentrations (relative to young individuals) after single or multiple doses. By far the majority of the available scientific data refer to the benzodiazepines, which have become the most widely prescribed class of sedative-anxiolytic drugs. Although there is not complete consistency in the available data, the weight of evidence indicates that old age is associated with impaired clearance of the benzodiazepines which are biotransformed by microsomal oxidation (such as diazepam, desmethyldiazepam, desalkylflurazepam, bromazepam, alprazolam, triazolam and others). For those benzodiazepines metabolised mainly by glucuronide conjugation (oxazepam, lorazepam, temazepam) or nitroreduction (nitrazepam), there are minimal, if any, age-related decrements in clearance. Only in the case of triazolam is there direct evidence linking impaired clearance to enhanced clinical effects in the elderly. The logical suggestion that benzodiazepines biotransformed by conjugation or by nitroreduction may be safer for the elderly than those biotransformed by oxidation has not yet been directly validated. Reasonable epidemiological evidence has linked the use of long (versus short) half-life benzodiazepines (regardless of the specific metabolic pathway) with an increased incidence of adverse reactions such as confusion, falls and hip fractures in elderly persons. However, the decreased clearance and increased accumulation of the benzodiazepines in question are not clearly validated as the cause of the increased frequency of adverse reactions.Old age may also be associated with an increased intrinsic sensitivity to benzodiazepines; that is, enhanced pharmacodynamic response, relative to young individuals, at any given plasma or target organ concentration. This change in sensitivity may coexist with, or be independent of, alterations in pharmacokinetics. Altered benzodiazepine sensitivity has been documented both in the course of clinical use of benzodiazepines prior to endoscopy or cardioversion, and in placebo-controlled laboratory trials. Animal models of aging have validated an enhanced response to benzodiazepines as a consequence of impaired clearance, increased intrinsic sensitivity or both. However, many studies directly assessing benzodiazepine receptor affinity, density and function in aging animals have failed to identify significant age-related changes.Despite substantial clinical and scientific data, few specific recommendations can be made regarding needed alterations in the approach to benzodiazepine therapy in elderly persons. Similarly, methodology is not yet available to identify precisely which elderly persons are at risk of developing adverse reactions to benzodiazepines. Clinical guidelines must still be based on the cautious approach of reduced dosage and careful monitoring of treatment.

Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice

Components of grapefruit juice may impair the activity of intestinal cytochrome P450 (CYP) 3A enzymes, sometimes resulting in clinically important drug interactions. The time course of recovery from CYP3A inhibition after a single exposure to grapefruit juice is not clearly established.