Plasma binding of benzodiazepines in humans.

Plasma binding of chlordiazepoxide, diazepam, loraxepam, and oxazepam was determined by equilibrium dialysis in 20 male, healthy volunteers, 25-86 years old. A wide range of binding was observed, with the free fraction varying twofold for lorazepam, fourfold for chlordiazepoxide and diazepam, and over 20-fold for oxazepam. Statistically significant linear relationships were not observed between the degree of binding and age, serum albumin, or total protein for any of the drugs. There was, however, a correlation between the extent of binding for the four drugs. Because of the importance of unbound benzodiazepine levels in eliciting any pharmacological response and also in disposition, consideration of the wide interindividual variability in plasma binding must be made in interpreting pharmacodynamic and pharmacokinetic data.     

Plasma testosterone concentrations in alcoholics.

Plasma testosterone concentrations were normal in 17 hospitalized alcoholics after a large dose of alcohol and in 16 Skid Row alcoholics. The findings fail to support the idea that the direct effects of alcohol on steroid metabolism cause gynecomastia and testicular atrophy.     

Plasma amiodarone concentrations during intravenous infusion.

Amiodarone is a useful antiarrhythmic agent whose pharmacokinetics are incompletely characterised. In order to optimise efficacy of an antiarrhythmic drug, information regarding plasma concentrations achieved during use of the drug is necessary. We report plasma amiodarone and desethylamiodarone concentrations in eight patients following intravenous infusion at a rate of 175 mg h-1 for the first 2 h, followed by infusion at a rate of 50 mg h-1 for a further 46 h a regimen very similar to that recommended by the manufacturers. In at least three of eight patients plasma concentrations were below the suggested therapeutic range of 1.0-2.5 mg l-1 from 3 to 16 h after the infusion was started. Our data suggests that larger doses of intravenous amiodarone than those previously recommended may be necessary to obtain optimal benefit from the drug.     

Impact of benzodiazepines on posaconazole serum concentrations. A population-based pharmacokinetic study on drug interaction

Abstract

Objectives:

Posaconazole is broadly used for antifungal prophylaxis and therapy. Current data suggest a concentration-dependent effect. Unlike other triazoles, cytochrome P450 is not a relevant route of biotransformation for posaconazole but glucuronidation, which might lead to a different spectrum of drug interactions. For benzodiazepines, the major metabolic pathway involves oxidation, but some, including lorazepam and temazepam, undergo conjugation to glucuronic acid.     

Plasma propranolol concentrations and the erythrocyte sedimentation rate.

1. The plasma propranolol concentrations after a single oral dose of 40 mg were measured in 25 patients with rheumatoid arthritis and compared with those of 16 patients with Crohn's disease from a previous study. Thirteen healthy volunteers were used as controls. 2. In both diseases some high and some low values occurred. This scatter did not correlate with any symptoms or biochemical or haematological data other than with the erythrocyte sedimentation rate (ESR). 3. Both sets of patients were therefore separated into two groups depending on whether or not their ESRs were above or below 20 mm/l h. In both diseases the plasma propranolol concentrations of the patients with a raised ESR were significantly higher than the controls as well as those of the low ESR group. 4. In rheumatoid arthritis the plasma propranolol concentrations of the patients with a low ESR did not differ from those of the controls, but in Crohn's disease they remained significantly higher. 5. In one patient with Crohn's disease there was a dramatic rise in propranolol concentrations during an exacerbation (ESR 91 mm/l h) compared with those during a remission (ESR 20 mm/l h). 6. A difference in smoking habits did not seem to have been responsible for the difference in plasma propranolol concentrations.     

Plasma concentrations of unbound phenytoin in the management of epilepsy.

In 46 epileptic patients the range of the unbound fraction of phenytoin in plasma measured by ultrafiltration (at 37 degrees C) and tracer-labelling with [14C]-phenytoin was 6.7%-33.3% with a median of 11.9%. The total and unbound phenytoin plasma concentrations were significantly correlated (r = 0.93, P less than 0.001), but in six patients the unbound concentration fell on or outside the 90% predictability limits for a single value. In all patients the unbound concentration reflected the clinical status of the patient equally or better than the total concentration. An inverse relationship was found between the plasma albumin concentration (within the normal reference range) and the phenytoin unbound fraction (r = -0.83, P less than 0.001) indicating that plasma albumin concentration is one of the important overall determinants of phenytoin protein binding. Saliva and plasma unbound phenytoin concentrations were significantly correlated (r = 0.98, P less than 0.001) but both collection of plasma samples and preparation of plasma ultrafiltrate using the Amicon micropartition system are simpler than collection and processing saliva, and interpretation of plasma unbound concentration does not require allowance for potential contamination. The additional value of the unbound phenytoin concentration in a clinically significant number of individuals would justify routine measurement of unbound phenytoin concentration in monitoring therapy, once available simplified methodology has been adequately characterised.     

Plasma diazepam and desmethyldiazepam concentrations during long-term diazepam therapy.

1 Factors influencing steady-state plasma concentrations of diazepam (DZ) and its major metabolite desmethyldiazepam (DMDZ) were assessed in 110 male Veterans Administration outpatient clinic patients (mean age 53 years). 2 Patients reportedly had taken DZ for 1 to 14 years (mean duration 5.1 years) at a mean daily dose of 20 mg (range 2 to 55 mg). 3 Steady-state plasma concentrations of DZ (mean 329 ng/ml) and DMDZ (mean 389 ng/ml) were highly correlated (r = 0.80), with a mean DMDZ/DZ ratio of 1.26. 4 Weight-corrected daily dose were significantly correlated with plasma level of DZ (r = 0.32), DMDZ (r = 0.38) and the sum of DZ plus DMDZ (r = 0.37), but explained a small fraction of individual variation. 5 Duration of therapy, smoking habits, alcohol consumption, and number of other drugs coingested were not significantly related to plasma level.     

Plasma concentrations of buprenorphine 24 to 72 hours after dosing.

BACKGROUND: This study evaluated plasma buprenorphine concentrations 24-72 h following sublingual administration of a dose of buprenorphine solution, ranging from 16 mg/70 kg to 44 mg/70 kg, administered on a daily or thrice-weekly schedule. Additionally, this study evaluated the effects of different thrice-weekly buprenorphine dose schedules on opiate use and withdrawal symptoms. METHODS: Opiate dependent subjects (n = 10) were maintained in an outpatient clinic for two 3-week periods at each of three thrice-weekly buprenorphine dose schedules (providing a weekly total buprenorphine dose of 64, 84 and 112 mg) and for 1 week of a daily buprenorphine dose of 16 mg/70 kg. Plasma samples were obtained 24, 48 and 72 h following administration of buprenorphine. Urine samples were also collected and opiate withdrawal symptoms, agonist effects and the use of heroin, cocaine, alcohol and other drugs, were assessed. RESULTS: Plasma levels showed a wide range of intra- and inter-subject variability. Nonetheless, higher doses of buprenorphine resulted in higher plasma concentrations at each time point and plasma concentration decreased with time. There were no significant differences in heroin use across dosing. Rates of withdrawal symptoms were low and did not differ across dosing schedules. CONCLUSIONS: In the two highest dose schedules, plasma levels 72 h following the administration of the highest dose and at 48 h after the lower dose, were comparable to plasma concentrations at 24 h following daily administration of 16 mg/70 kg of buprenorphine.     

Plasma concentrations of diazepam and desmethyldiazepam during chronic diazepam therapy.

1 Plasma concentrations of diazepam and its metabolite, desmethyldiazepam, have been measured in both in- and out-patient groups treated with diazepam for periods varying between 1 month and 10 years. 2 The diazepam concentration was directly related to the dose of diazepam ingested and inversely related to the age of the patient. 3 A highly significant relationship was obtained between the concentration of desmethyldiazepam and diazepam. 4 The plasma concentrations of both diazepam and its metabolite were independent of sex, duration fo therapy and patient group.     

Toxicological determination of benzodiazepines in serum: methods and concentrations associated with high-dose intravenous therapy with diazepam.

This paper describes a rapid and simple procedure for the determination of benzodiazepines in biological samples. Five common benzodiazepines (diazepam, oxazepam, clorazepate, flurazepam, and chlordiazepoxide) and/or their major metabolites are extracted from a buffered serum sample at pH 9.2 by a mixture of toluene, hexane, and isoamyl alcohol. The phases are separated by centrifugation, and a small aliquot of the organic layer is injected into a gas chromatograph equipped with an electron-capture detector. The drugs are identified and quantitated by comparison with standards simultaneously processed similarly. A sample can be analyzed in about 30 min. The technique is illustrated by its application to sequential samples from a patient being treated for delirium tremens with large intravenous doses of diazepam. Serum diazepam, N-desmethyldiazepam, and oxazepam concentrations several times higher than usually encountered therapeutically were observed.     

Pharmacokinetics of closely related benzodiazepines.

1 It is commonplace for drugs to vary by only minor chemical differences. This is particularly so for those seven benzodiazepines discussed in this paper which are related both as precursors and as metabolites. However, minor chemical differences may cause major differences in physicochemical and pharmacodynamic properties. 2 Although the physicochemical differences are difficult to relate to effect, the influence of structure on absorption, distribution and elimination is of considerable importance in governing duration of effect, as shown by studies in monkeys and in man. This in turn dictates the suitability of a particular drug as a day or night sedative, as an anticonvulsant, or as an anxiolytic. 3 Structure affects the relative potency of the compounds as anticonvulsants, anxiolytics or sedatives so that judicious choice of a particular compound for a particular patient and condition will lead to improved therapy. It is fallacious to consider all benzodiazepines as similar.     

Plasma drug concentrations and physiological measures in 'dance party' participants.

The increasing use of (+/-) 3,4-methylenedioxymethamphetamine (MDMA) in the setting of large dance parties ('raves') and clubs has been the source of some concern, because of potential acute adverse events, and because animal studies suggest that MDMA has the potential to damage brain serotonin (5-HT) neurons. However, it is not yet known whether MDMA, as used in the setting of dance parties, leads to plasma levels of MDMA that are associated with toxicity to 5-HT neurons in animals. The present study sought to address this question. Plasma MDMA concentrations, vital signs, and a variety of blood and urine measures were obtained prior to, and hours after, individuals attended a dance party. After the dance party, subjects were without clinical complaints, had measurable amounts of residual MDMA in plasma, and nearly half of the subjects also tested positive for methamphetamine, another amphetamine analog that has been shown to have 5-HT neurotoxic potential in animals. Plasma concentrations of MDMA did not correlate with self-reported use of 'ecstasy' and, in some subjects, overlapped with those that have been associated with 5-HT neurotoxicity in non-human primates. Additional subjects were likely to have had similar concentrations while at the dance party, when one considers the reported time of drug ingestion and the plasma half-life of MDMA in humans. Hematological and biochemical analyses were generally unremarkable. Moderate increases in blood pressure, heart rate and body temperature were observed in the subjects with the highest MDMA plasma concentrations. These findings are consistent with epidemiological findings that most people who use MDMA at dance parties do not develop serious clinical complications, and suggest that some of these individuals may be at risk for developing MDMA-induced toxicity to brain serotonin neurons.     

Plasma metronidazole concentrations after single and repeated vaginal pessary administration.

Metronidazole concentrations in plasma were measured by h.p.l.c. in 12 healthy female volunteers after single and repeated vaginal administration of 500 mg metronidazole pessaries. The area under the plasma concentration-time curve (AUC(0,12 h) was 8.4 +/- 3.9 micrograms ml-1 h (mean +/- s.d.) on day 1 and 20.6 +/- 7.1 micrograms ml-1 h (mean +/- s.d.) on day 5. The peak plasma drug concentration on day 1 was 1.2 +/- 0.6 micrograms ml-1 (mean +/- s.d.) and on day 5 it was 2.0 +/- 0.7 micrograms ml-1 (mean +/- s.d.). The plasma concentration of metronidazole at steady state was above the minimum inhibitory concentration (MIC) for anaerobic Streptococci and Clostridium tetani. These results demonstrate much lower systemic exposure than after oral administration.     

Plasma concentrations of diphenylhydantoin in young infants

Summary Plasma concentrations of diphenylhydantoin (DPH) were measured in six infants, 3 to 78 days old, who received about 10 mg/kg/day, orally or intramuscularly because of convulsions. Unexpectedly, the levels found were only half of those noted previously in adults treated with 5 mg/kg/day.