Population Pharmacokinetics of High-Dose Oxazepam in Alcohol-Dependent Patients: Is There a Risk of Accumulation?

BACKGROUND: According to the guidelines, benzodiazepines with a short half-life are the reference medication to treat alcohol withdrawal syndrome. The doses of oxazepam used in this population may reach up to 300 mg per day, significantly higher than usual doses. Its use in these patients deserves further information to confirm that the half-life remains constant and that no accumulation appears. The objective of this study was to investigate the pharmacokinetics of high doses of oxazepam in alcohol-dependent patients treated for alcohol withdrawal syndrome. METHODS: Overall, 63 outpatients [weight, 71.1 kg (45.0-118.0); age, 47.6 years (31-67)] followed in the addictology unit, were studied. Total mean dose of 96.0 mg per day (range, 20-300 mg/d) was administered by oral route. Therapeutic drug monitoring allowed the measurement of 96 plasma concentrations. The following covariates were evaluated: demographic data (age, body weight, height, gender) and biological data (creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase). Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model. RESULTS: Data were modeled with a 1-compartment pharmacokinetic model. The population typical mean 90% confidence interval values for clearance, apparent volume of distribution (V), and duration of absorption (D1) were 6.8 L/h (range, 3.9-8.0 L/h), 159 L (range, 98.0-282 L), and 2 hours (fixed), respectively. The interindividual variability of clearance and V, and residual variability (90% confidence interval) were 74% (44%-96%), 69% (40%-89%), and 32% (20%-41%), respectively. The elimination half-life was 16 hours (range, 3-42 hours). CONCLUSIONS: Oxazepam exhibited a linear pharmacokinetics with a proportional relationship from 20 to 300 mg per day, the dose range currently used in alcohol-dependent patients treated for alcohol withdrawal syndrome. We did not find any evidence of drug accumulation with these doses.

Pharmacokinetics of the cytochrome P-450 substrates phenytoin, theophylline, and diazepam in healthy Greyhound dogs.

The purpose of this study was to determine the pharmacokinetics of phenytoin, theophylline, and diazepam in six healthy Greyhound dogs. Additionally, the pharmacokinetics of the diazepam metabolites, oxazepam and nordiazepam, after diazepam administration was determined. Phenytoin sodium (12 mg/kg), aminophylline (10 mg/kg), and diazepam (0.5 mg/kg) were administered IV on separate occasions, and blood was collected at predetermined time points for the quantification of plasma drug concentrations by fluorescence polarization immunoassay (phenytoin, theophylline) or mass spectrometry (diazepam, oxazepam, and nordiazepam). The terminal half-life was 4.9, 9.2, and 1.0 h, respectively, for phenytoin, theophylline, and diazepam, and 6.2 and 2.4 h for oxazepam and nordiazepam after IV diazepam. The clearance was of 2.37, 0.935, and 27.9 mL · min/kg, respectively, for phenytoin, theophylline, and diazepam. The C(MAX) was 44.7 and 305.2 ng/mL for oxazepam and nordiazepam, respectively, after diazepam administration. Temazepam was not detected above 5 ng/mL in any sample after IV diazepam.

Diazepam pharmacokinetics after nasal drop and atomized nasal administration in dogs.

The standard of care for emergency therapy of seizures in veterinary patients is intravenous (i.v.) administration of benzodiazepines, although rectal administration of diazepam is often recommended for out-of-hospital situations, or when i.v. access has not been established. However, both of these routes have potential limitations. This study investigated the pharmacokinetics of diazepam following i.v., intranasal (i.n.) drop and atomized nasal administration in dogs. Six dogs were administered diazepam (0.5 mg/kg) via all three routes following a randomized block design. Plasma samples were collected and concentrations of diazepam and its active metabolites, oxazepam and desmethyldiazepam were quantified with high-performance liquid chromatography (HPLC). Mean diazepam concentrations >300 ng/mL were reached within 5 min in both i.n. groups. Diazepam was converted into its metabolites within 5 and 10 min, respectively, after i.v. and i.n. administration. The half lives of the metabolites were longer than that of the parent drug after both routes of administration. The bioavailability of diazepam after i.n. drop and atomized nasal administration was 42% and 41%, respectively. These values exceed previously published bioavailability data for rectal administration of diazepam in dogs. This study confirms that i.n. administration of diazepam yields rapid anticonvulsant concentrations of diazepam in the dog before a hepatic first-pass effect.

[Simultaneous determination of 5 sedative hypnotics in human plasma by reversed phase high-performance liquid chromatography].

OBJECTIVE: To determine diazepam, nitrazepam, oxazepam, estazolam, and alprazolam simultaneously in human plasma by reversed phase high-performance liquid chromatography (RP-HPLC). METHODS: Ten microliter carbamazepine (50 mg/L)as the internal standard was added into 1 mL sample, which contained the 5 mixed sedative hypnotics as standard substance and human plasma as ground substance. They were extracted with acetoacetate from plasma samples, and then were dissolved by 100 microL mobile phase. The blood drug levels were analyzed by high performance liquid chromatograph with 20 microL sample injection on a chromatographic column C18 (4.6 mm x 250 mm) at 30 degree. The mobile phase consisted of methanol and water (65:35),and the flow rate was 1.0 mL/min.The ultraviolet detection wavelength was 230 nm. RESULTS: The linearity range of the 5 drugs was 5-1,200 microg/L (r> or =0.9966, P<0.05). The recovery rate was 95.5%-105.6%. The extraction recovery rate was more than 75%. The relative standard deviation (RSD) of intra-day and inter-day was less than 10% (n=5). CONCLUSION: RP-HPLC method is convenient, accurate and sensitive for simultaneous determination of the concentration of diazepam, nitrazepam, oxazepam, estazolam, and alprazolam in human plasma.

Quantitation of benzodiazepines in urine, serum, plasma, and meconium by LC-MS-MS.

A single method for confirmation and quantitation of a panel of commonly prescribed benzodiazepines and metabolites, alpha-hydroxyalprazolam, alpha-hydroxyethylflurazepam, alpha-hydroxytriazolam, alprazolam, desalkylflurazepam, diazepam, lorazepam, midazolam, nordiazepam, oxazepam, temazepam, clonazepam, and 7-aminoclonazepam, was developed for three specimen types, urine, serum/plasma, and meconium. Quantitation was by liquid chromatography tandem-mass spectrometry (LC-MS-MS) using a Waters Alliance-Quattro Micro system. The instrument was operated in multiple reaction monitoring mode with an electrospray ionization source in positive ionization mode. The method was evaluated for recovery, imprecision, linearity, analytical measurement range, specificity, and carryover. Average recovery and imprecision (within-run, between-run, and total % CV) were within +/- 15% of the target concentrations for urine (10 to 5000 ng/mL) and serum/plasma (10 to 2500 ng/mL) and within +/- 20% for meconium (10 to 5000 ng/g). In all, 205 patient specimens were analyzed, and the results compared to a previous in-house gas chromatography-MS method or LC-MS-MS results from an outside laboratory. Oxazepam glucuronide was evaluated as a hydrolysis control for the urine and meconium specimens.

Cardiac and peripheral blood similarities in the comparison of nordiazepam and bromazepam blood concentrations.

Concomitant heart and peripheral blood determinations were performed on 40 fatal cases involving nordiazepam (20 cases) and bromazepam (20 cases). The heart blood concentration for the two drugs (588 ng/mL for nordiazepam and 802 ng/mL for bromazepam) does not differ from the corresponding peripheral blood concentration (587 ng/mL for nordiazepam and 883 ng/mL for bromazepam). The mean ratios for the heart and peripheral blood concentrations were 0.95 for nordiazepam and 0.86 for bromazepam. No postmortem redistribution was observed for these two benzodiazepines. The authors thus suggest that corresponding heart blood can be proposed in the quantitative analysis of these drugs when peripheral blood is unavailable. The present study also shows the stability of the two drugs after a year of storage.

Associations between use of benzodiazepines or related drugs and health, physical abilities and cognitive function: a non-randomised clinical study in the elderly.

OBJECTIVE: To describe associations between the use of benzodiazepines or related drugs (BZDs/RDs) and health, functional abilities and cognitive function in the elderly. METHODS: A non-randomised clinical study of patients aged > or =65 years admitted to acute hospital wards during 1 month. 164 patients (mean age +/- standard deviation [SD] 81.6 +/- 6.8 years) were admitted. Of these, nearly half (n = 78) had used BZDs/RDs before admission, and the remainder (n = 86) were non-users. Cognitive ability was assessed by the Mini-Mental State Examination (MMSE). Patients scoring > or =20 MMSE sum points were interviewed (n = 79) and questioned regarding symptoms and functional abilities during the week prior to admission. Data on use of BZDs/RDs before admission, current medications and discharge diagnoses were collected from medical records. Health, physical abilities and cognitive function were compared between BZD/RD users and non-users, and adjustments were made for confounding variables. The residual serum concentrations of oxazepam, temazepam and zopiclone were analysed. RESULTS: The mean +/- SD duration of BZD/RD use was 7 +/- 7 years (range 1-31). Two or three BZDs/RDs were concomitantly taken by 26% of users (n = 20). Long-term use of these drugs was associated with female sex and use of a higher number of drugs with effects on the CNS, which tended to be related to diagnosed dementia. After adjustment for these variables as confounders, use of BZDs/RDs was not associated with cognitive function as measured by the MMSE. However, use of BZDs/RDs was associated with dizziness, inability to sleep after awaking at night and tiredness in the mornings during the week prior to admission and with stronger depressive symptoms measured at the beginning of the hospital stay. Use of BZDs/RDs tended to be associated with a reduced ability to walk and shorter night-time sleep during the week prior to admission. A higher residual serum concentration of temazepam correlated with a lower MMSE sum score after adjustment for confounding variables. CONCLUSIONS: Long-term use and concomitant use of more than one BZD/RD were common in elderly patients hospitalised because of acute illnesses. Long-term use was associated with daytime and night-time symptoms indicative of poorer health and potentially caused by the adverse effects of these drugs.

New high-performance liquid chromatographic method for serum analysis of oxazepam: application to bioequivalence and pharmacokinetic study.

A rapid and sensitive high-performance liquid chromatographic method was developed and validated for determination of oxazepam in serum. Oxazepam was isolated from biological fluid using a simple liquid-liquid extraction with dichloromethane. Nordazepam was used as the internal standard. The chromatographic separation was accomplished using a 125 x 4-mm (inner diameter) stainless-steel (5 microm) Perfectsil Target ODS-3 reversed phase column with a mobile phase consisting of ammonium dihydrogen phosphate buffer (0.05 mol x L(-1), pH 5.8) and methanol (50:50, v/v), running at a flow rate of 1.5 ml x min(-1). The absorbance of the fluent was monitored at 254 nm. The developed method resulted in totally symmetrical peaks. It has been applied to assess the pharmacokinetics of oxazepam. Also the bioequivalence of two different oxazepam preparations following oral administration in healthy volunteers was assessed by this method.

Site-, Technique-, and Time-Related Aspects of the Postmortem Redistribution of Diazepam, Methadone, Morphine, and their Metabolites: Interest of Popliteal Vein Blood Sampling.

Sampling site, technique, and time influence postmortem drug concentrations. In 57 cases, we studied drug concentration differences as follows: subclavian vein-dissection/clamping versus blind stick, femoral vein-dissection/clamping versus blind stick, right cardiac chamber, and popliteal vein-dissection and clamping only. Cases were distributed in group #1 (all cases with both techniques), group #2 (dissection/clamping), and group #3 (blind stick). Sampled drugs were diazepam, methadone, morphine, and their metabolites. To assess PMR, mean concentrations and ratios were calculated for each group. Time-dependent variations of blood concentrations and ratios were also assessed. Results indicate that site, method, and time may influence postmortem distribution interpretation in different ways. Popliteal blood seems less subject to PMR. In conclusion, our study is the first to evaluate concurrently three main aspects of PMR and confirms that the popliteal vein may represent a site that is more resistant to the changes seen as a result of PMR.

Liquid chromatographic-electrospray ionization mass spectrometric quantitative analysis of buprenorphine, norbuprenorphine, nordiazepam and oxazepam in rat plasma.

A liquid chromatographic-mass spectrometric method with electrospray ionization is presented for the simultaneous determination of buprenorphine, nordiazepam and their pharmacologically active metabolites, norbuprenorphine and oxazepam, in rat plasma. The drugs were extracted from plasma by liquid-liquid extraction and chromatographically separated using a gradient elution of aqueous ammonium formate and acetonitrile. Following electrospray ionization, the analytes were quantified in the single ion storage mode. The assay was validated according to current acceptance criteria for bioanalytical method validation. It was proved to be linear from 0.7 to 200 ng/ml plasma for buprenorphine, 1.0 to 200 ng/ml for norbuprenorphine, 2.0 to 200 ng/ml for nordiazepam, and from 5.0 to 200 ng/ml for oxazepam. The average recoveries of buprenorphine, norbuprenorphine, nordiazepam and oxazepam were 89, 39, 88 and 82%, respectively, with average coefficients of variation ranging from 1.8 to 14.3%. The limits of quantitation for these drugs were 0.7, 1.0, 2.0 and 5.0 ng/ml, respectively, with associated precisions within 17% and accuracies within +/-18% of the nominal values. Both the intra- and inter-assay precision values did not exceed 11.3% for the four analytes. Intra- and inter-assay accuracies lay within +/-15% of the nominal values. The validated method was applied to the determination of buprenorphine, norbuprenorphine, nordiazepam and oxazepam in plasma samples collected from rats at various times after intravenous administration of buprenorphine and nordiazepam.

Anti-anxiety drugs and fish behavior: Establishing the link between internal concentrations of oxazepam and behavioral effects.

Psychoactive drugs are frequently detected in the aquatic environment. The evolutionary conservation of the molecular targets of these drugs in fish suggests that they may elicit mode of action-mediated effects in fish as they do in humans, and the key open question is at what exposure concentrations these effects might occur. In the present study, the authors investigated the uptake and tissue distribution of the benzodiazepine oxazepam in the fathead minnow (Pimephales promelas) after 28 d of waterborne exposure to 0.8 µg L-1 , 4.7 µg L-1 , and 30.6 µg L-1 . Successively, they explored the relationship between the internal concentrations of oxazepam and the effects on fish exploratory behavior quantified by performing 2 types of behavioral tests, the novel tank diving test and the shelter-seeking test. The highest internal concentrations of oxazepam were found in brain, followed by plasma and liver, whereas muscle presented the lowest values. Average concentrations measured in the plasma of fish from the 3 exposure groups were, respectively, 8.7 ± 5.7 µg L-1 , 30.3 ± 16.1 µg L-1 , and 98.8 ± 72.9 µg L-1 . Significant correlations between plasma and tissue concentrations of oxazepam were found in all 3 groups. Exposure of fish to 30.6 µg L-1 in water produced plasma concentrations within or just below the human therapeutic plasma concentration (HT PC) range in many individuals. Statistically significant behavioral effects in the novel tank diving test were observed in fish exposed to 4.7 µg L-1 . In this group, plasma concentrations of oxazepam were approximately one-third of the lowest HT PC value. No significant effects were observed in fish exposed to the lowest and highest concentrations. The significance of these results is discussed in the context of the species-specific behavior of fathead minnow and existing knowledge of oxazepam pharmacology. Environ Toxicol Chem 2016;35:2782-2790. © 2016 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Development and validation of a liquid chromatographic/electrospray ionization mass spectrometric method for the quantitation of prazepam and its main metabolites in human plasma.

A method was developed and fully validated for the quantitation of prazepam and its major metabolites, oxazepam and nordiazepam, in human plasma. Sample pretreatment was achieved by solid-phase extraction using Oasis HLB cartridges. The extracts were analysed by high-performance liquid chromatography (HPLC) coupled with single-quadrupole mass spectrometry (MS) with an electrospray ionization interface. The MS system was operated in the selected ion monitoring mode. HPLC was performed isocratically on a reversed-phase XTerra MS C18 analytical column (150 x 3.0 mm i.d., particle size 5 microm). Diazepam was used as the internal standard for quantitation. The assay was linear over a concentration range of 5.0-1000 ng ml(-1) for all compounds analyzed. The limit of quantitation was 5 ng ml(-1) for all compounds. Quality control samples (5, 10, 300 and 1000 ng ml(-1)) in five replicates from three different runs of analysis demonstrated an intra-assay precision (CV) of < or = 9.1%, an inter-assay precision of < or = 6.0% and an overall accuracy (relative error) of < 4.6%. The method can be used to quantify prazepam and its metabolites in human plasma covering a variety of pharmacokinetic or bioequivalence studies.

Interindividual variability in the glucuronidation of (S) oxazepam contrasted with that of (R) oxazepam.

Although conjugation with glucuronic acid is a major process for converting many xenobiotics into hydrophilic, excretable metabolites, relatively little has been reported concerning interindividual variability of glucuronidation in human populations. Oxazepam, a therapeutically active metabolite of diazepam, is one of a number of C3-hydroxylated benzodiazepines for which glucuronide conjugation is the predominant pathway of biotransformation. The drug is normally formulated as a racemic mixture of inactive (R) and active (S) enantiomers. In the present study we have investigated the use of oxazepam as a potential probe drug for studying the variability of glucuronide conjugation, and for demonstrating the extent to which genetic factors may be responsible. In preliminary studies we determined oxazepam pharmacokinetics metabolite profiles after administration of racemic (R,S) oxazepam to eleven human volunteers. The (S) glucuronide was preferentially formed and excreted in nine of the eleven subjects. The ratios of (S) to (R) glucuronide metabolites (S/R ratios) were 3.87 +/- 0.79 (mean +/- SD) and 3.52 +/- 0.60 in urine and plasma, respectively. However, both ratios were significantly lower in two subjects (p < 0.01). In these two atypical subjects, the half-life of (R,S) oxazepam was also markedly longer (14.7 and 15.9 h) than in the other subjects (8.1 +/- 3.2 h). A good correlation (rs = 0.90) between the S/R-glucuronide ratio in urine and the plasma clearance of (R,S) oxazepam suggested that a low S/R ratio may be a marker of poor elimination of oxazepam. In further investigations, the drug was administered to 66 additional subjects. The S/R-glucuronide ratio in 8 h pooled urine was bimodally distributed, with 10% of all subjects possessing ratios below an apparent antimode of 1.9. A survey of the in vitro formation of oxazepam glucuronides by microsomes from 37 human livers also showed that 10% of the livers displayed an abnormally high apparent Michaelis constant (Km) for the formation of the (S) glucuronide, but not of the (R) glucuronide. These results suggest that the glucuronidation of the pharmacologically active (S) enantiomer of oxazepam is decreased in a significant percentage (10%) of Caucasian individuals. The observed in vitro differences in apparent kinetics of the S-glucuronidation reaction may reflect defects at the genetic level, leading to structural changes in the isozyme(s) of UDP-glucuronyltransferase that catalyse this reaction.

Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives.

Women on low-dose estrogen oral contraceptives (OC) and drug-free control women matched for age, weight, and cigarette smoking habits, received single 2-mg IV doses of lorazepam or single 30-mg oral doses of oxazepam, two benzodiazepines metabolized by glucuronide conjugation. Kinetics were determined from multiple plasma concentrations measured during 48 hr after dosing. Mean kinetic variables for lorazepam in control and OC groups (n = 15 in each group) were: volume of distribution (Vd), 1.33 and 1.45 l/kg; elimination t1/2, 13.1 and 12.2 hr; total clearance, 1.25 and 1.50 ml/min/kg; free fraction in plasma, 10.3% and 10.3% unbound. For oxazepam, kinetic variables in the two groups (n = 14 and 17) were: Vd, 1.05 and 1.19 l/kg; t1/2, 7.6 and 7.2 hr; total clearance, 1.60 and 2.03 ml/min/kg; free fraction, 4.6% and 4.9% unbound. None of these differences were significant. Thus, metabolic clearance by glucuronidation of lorazepam and oxazepam is not significantly affected by OC, in contrast with the highly significant reduction in clearance of the oxidized benzodiazepine diazepam.

PIP: Women taking low-dose estrogen oral contraceptives (OCs) and drug-free control women matched for age, weight, and cigarette smoking habits, received single 2-mg intravenous doses of lorazepam or single 30-mg oral doses of oxazepam, 2 benzodiazepines metabolized by glucuronide conjugation. Kinetics were determined from multiple plasma concentrations measured during the 48 hours after dosing. Mean kinetic variables for lorazepam in control and OC groups (n=15 in each group) were: volume of distribution (Vd), 1.33 and 1.45 1/kg; elimination t1/2, 13.1 and 12.2 hours; total clearance, 1.25 and 1.50 ml/minute/kg; free fraction in plasma, 10.3% and 10.3% unbound. For oxazepam, kinetic variables in the 2 groups (n=14 and 17) were: Vd, 1.05 and 1.19 1/kg; t1/2, 7.6 and 7.2 hours; total clearance, 1.60 and 2.03 ml/minute/kg); free fraction, 4.6% and 4.9% unbound. None of these differences were significant. Thus, metabolic clearance by glucuronidation of lorazepam and oxazepam is not significantly affected by OCs, in contrast with the highly significant reduction in clearance of the oxidized benzodiazepine diazepam.

Effect of brussels sprouts and cabbage on drug conjugation.

Ten healthy subjects were fed three diets for 10 days each: a control diet, a cabbage and brussels sprouts--containing diet, and the control diet a second time. Oxazepam was taken on day 7 and acetaminophen on day 10 of each dietary regimen. The test diet stimulated the metabolism of acetaminophen, at least in part by enhanced glucuronidation, as evidenced by a 16% decrease in mean plasma AUC, a 17% increase in mean metabolic clearance rate, an increased ratio of acetaminophen glucuronide to acetaminophen in plasma from 1 to 11 hr after drug and an 8% increase in mean 24-hr urinary recovery of acetaminophen glucuronide, which returned toward control when the subjects were fed the control diet a second time. There were no comparable changes in the metabolism of acetaminophen to acetaminophen sulfate. When the subjects ate the test diet, 24-hr urinary recovery of the cysteine conjugate and of 3-methoxyacetaminophen sulfate, end-products of minor oxidative pathways, the former involving a toxic intermediate, decreased 13% and 22%. Cabbage and brussels sprouts induced a 17% decrease in mean plasma AUC and a 19% increase in mean metabolic clearance rate for oxazepam, but there was no change in mean plasma t1/2 for this drug, nor was there a change in ratio in plasma of oxazepam glucuronide to oxazepam.

Massive benzodiazepine requirements during acute alcohol withdrawal.

Severe alcohol withdrawal developed in an abstinent chronic alcoholic man. Massive doses of benzodiazepines (2,335 mg of diazepam intravenously, 21,225 mg of oxazepam orally) achieved only marginal control of delirium and agitation. Analysis of multiple blood samples drawn during and after the withdrawal episode indicated, as expected, very high concentrations of diazepam and metabolites and of oxazepam. There was no evidence of an abnormal pharmacokinetic profile. Benzodiazepine resistance in withdrawing alcoholics probably reflects a receptor-site phenomenon rather than an abnormal drug disposition.

Nighttime and daytime efficacy of flurazepam and oxazepam in chronic insomnia.

Trials of hypnotic medications typically determine efficacy by examining changes in polysomnographically recorded sleep and in daytime performance. The authors employed daytime sleepiness as a new, potentially crucial criterion in such trials. Oxazepam and flurazepam were effective in improving some polysomnographically defined measures of nocturnal sleep in 14 patients with chronic insomnia; flurazepam produced substantial daytime sleepiness and oxazepam did not. Oxazepam produced some rebound insomnia, consisting of about an hour's reduction of polysomnographically defined sleep, but without gross mood disturbance or the patients' awareness of sleep loss.

Influence of benzodiazepines on auditory perception.

The aim of this study was to test for an influence of benzodiazepine (BZD) on various perceptual and/or cognitive auditory processes. Loudness, auditory selective attention, and the ability of subjects to form perceptual streams out of alternating tone sequences were tested. Nine subjects were tested before, 1, 3, 7, and 24 h after a single-dose oxazepam vs placebo administration in a crossover design. A sample of blood allows us to measure plasma oxazepam concentration. The results revealed a significant reduction in stream segregation expressed as d' scores 1 h after oxazepam intake in the test subjects. No significant change occurred across time in the same subjects when they were administrated a placebo in another session. Furthermore, oxazepam had no substantial and systematic influence either on auditory selective attention or on loudness perception. Altogether, these results suggest that the perceptual organization of sound sequences involves inhibitory neural mechanisms, which can be affected by BZDs. This outcome is consistent with existing models of auditory stream segregation and may be paralleled with earlier findings on the effect of BZDs on perceptual binding in the visual modality.

Oxazepam esters. 2. Correlation of hydrophobicity with serum binding, brain penetration, and excretion.

Pharmacokinetics of a series of prodrug-type oxazepam esters were studied in mice. The effect of hydrophobicity was investigated in relation to serum binding, brain penetration, tissue storage, and excretion. Binding to mouse serum and to human serum albumin was measured by equilibrium dialysis, and the changes in binding free energy were correlated with RM values. Brain-blood partition of the esters did not change parallel with their serum binding. An indirect correlation exists between RM of the esters and oxazepam brain accrual. Brain-blood concentration ratios of oxazepam prove that hydrolysis precedes brain penetration and hydrophobicity might primarily influence the hydrolysis rate. The amount of tissue storage and total excretion rates also correlate with hydrophobicity.

Distribution of diazepam, nordiazepam, and oxazepam between brain extraneuronal space, brain tissue, plasma, and cerebrospinal fluid in diazepam and nordiazepam dependent dogs.

The compartmental distribution of diazepam (DZ) and nordiazepam (ND) and their metabolites was studied in DZ and ND dependent dogs. The levels of DZ, and ND and their metabolites were determined during the last week of stabilization in the extraneuronal brain space, in brain tissue, in plasma and in CSF. In these studies dependent dogs were anesthetized with pentobarbital and microdialysis probes were inserted bilaterally into the parietal cortex and perfused with artificial cerebrospinal fluid. Microdialysis probes were also used to determine the unbound parent drugs and their metabolites in plasma. The brain-plasma distribution of total ND and oxazepam (OX) is about equal in ND dependent dogs but in DZ dependent dogs total ND and OX are about 2-fold higher in brain than in plasma. The levels of DZ, ND, and OX in the extraneuronal brain space are similar to their unbound levels in plasma. These data suggest that the concentration of free benzodiazepines in plasma is a good approximation of the concentration in the vicinity of the membrane receptors in the dependent dogs.