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To assess pharmacodynamic and neurochemical aspects of tolerance, lorazepam (2 mg/kg/day), or vehicle was administered chronically to male Crl: CD-1(ICR)BR mice via implantable osmotic pump. Open-field behavior, benzodiazepine receptor binding in vitro, receptor autoradiography, and muscimol-stimulated chloride uptake were examined at both 1 and 14 days. Open-field activity was depressed in lorazepam-treated animals on Day 1. On Day 14, open-field parameters were indistinguishable from those of vehicle-treated animals, indicating behavioral tolerance. Benzodiazepine binding, as determined by the specific binding of [125I]diazepam, was also decreased in cortex on Day 14. Hippocampal binding was unchanged following chronic lorazepam exposure. Apparent affinity in cortical membrane preparations was unchanged, indicating that altered ligand uptake was due to decreased receptor number. Muscimol-stimulated chloride uptake into cortical synaptoneurosomes from lorazepam-treated animals was not significantly different on Day 1 or Day 14 compared to vehicle-treated animals. These results confirm that down-regulation of benzodiazepine receptor binding is closely associated with behavioral tolerance to benzodiazepines. These observed changes in binding are not necessarily associated with robust changes in receptor function.

Objective: To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point., Methods: Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 microg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs., Results: The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins., Conclusion: Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.

To characterize the potential interaction between the excitatory and inhibitory neurotransmitter systems, the effects of dizocilpine, CPP, and lorazepam on open-field behavior and pentylenetetrazol-induced seizures were evaluated in mice. Dizocilpine (0.01-0.1 mg/kg), CPP (1-10 mg/kg), or vehicle was administered intraperitoneally 15 min prior to lorazepam (0.2-2 mg/kg) or vehicle. Behavioral monitoring began 25 min after the lorazepam injection. Upon completion of testing, unrestrained mice were infused intravenously with pentylenetetrazole until the onset of a full tonic-clonic seizure. The highest dose of dizocilpine by itself significantly increased the average distance traveled, the number of rears, and the number of stereotypies during the test period. Lorazepam alone dose dependently decreased activity on all behavioral parameters. Lorazepam also completely antagonized the hyperactivity produced by dizocilpine when the two compounds were coadministered. This antagonism is most likely due to an interaction in the regulation of dopaminergic tone which underlies motor activity. Lorazepam exerted a dose-dependent anticonvulsant effect. Dizocilpine alone had no effect on seizure induction and did not potentiate the anticonvulsive effect of lorazepam when coadministered with lorazepam. CPP reduced the number of rears and the number of stereotypies during the test period. CPP did not alter the pentylenetetrazol-induced seizure threshold and did not influence the anticonvulsant effect of lorazepam.

Benzodiazepine discontinuation is associated with alterations in motor activity and gamma-aminobutyric acid-A receptor upregulation in a mouse model. Prior studies indicate that concurrent administration of the compound N-methyl-N-(methyl-1-propyl)chloro-2-phenyl-1-isoquinoline-3- carboxamide (PK1195), a "peripheral" site benzodiazepine antagonist, can attenuate the effects of lorazepam on tolerance and receptor alterations. To evaluate the effects of PK11195 administration on benzodiazepine discontinuation, we administered lorazepam (2 mg/kg per day), PK 11195 (1 to 10 mg/kg per day) or the combination to mice for 7 days, and then evaluated pentylenetetrazole-induced seizure threshold and benzodiazepine binding at days 1, 4, and 7 after discontinuation. Seizure threshold was reduced at 4 days after lorazepam discontinuation; this effect was attenuated by coadministration of PK11195 at 5 mg/kg per day. Lorazepam discontinuation effects were not altered by PK11195 at 1 mg/kg per day, whereas the 10-mg/kg dose was not different from 5 mg/kg per day. The competitive ligand Ro5-4864 at 10 mg/kg per day, blocked the effects of PK11195 on lorazepam discontinuation. Benzodiazepine receptor binding in vivo was increased in the cortex and hippocampus at 4 days postlorazepam discontinuation. This effect was attenuated in the hippocampus but not in the cortex by concurrent administration of PK1195. These data indicate that concurrent administration of PK11195 may attenuate discontinuation effects of lorazepam.

The behavioral effects of two beta-adrenergic receptor antagonists, selected to represent differing lipophilicity, were evaluated in a double-blind, single-dose, parallel-group study. A group of 55 healthy volunteers (mean age, 28 years) received single oral doses of placebo, atenolol (50 mg), propranolol (40 mg), or lorazepam (2 mg). Plasma drug concentrations, self-ratings of sedation and mood, observer ratings of sedation, and performance on the Digit Symbol Substitution Test (DSST) were assessed at multiple times during 24 hours after drug administration. Information acquisition and recall were tested at 3 and 24 hours after drug administration. Lorazepam significantly increased sedation and fatigue, impaired DSST performance, and impaired memory. The time course of these changes was highly consistent with plasma lorazepam concentrations. In contrast, atenolol and propranolol produced at most small changes in self-ratings and observer ratings and did not alter DSST performance or memory. Under experimental conditions that are sensitive to the depressant effects of a typical benzodiazepine, single doses of atenolol and propranolol produced no meaningful changes, compared with placebo.

Tolerance to the sedative and anticonvulsant effects of benzodiazepines has been reported, but cross-tolerance among benzodiazepines is poorly characterized. To evaluate cross-tolerance between lorazepam and alprazolam in a reliable anticonvulsant pharmacodynamic model, we treated mice with either drug for 14 days, and with the two drugs sequentially for 7 days each. Pentylenetetrazole-induced seizure thresholds were similar in mice treated for 14 days with lorazepam or alprazolam, 2 mg/kg/day. For both compounds, a discontinuation effect characterized by reduced seizure threshold occurred at 4 days after discontinuation. Substitution of alprazolam for lorazepam after 1 week, and vice versa, did not interrupt tolerance. [3H]flumazenil binding in vivo was downregulated in cortex after 14 days of either drug. However, binding was also reduced in hippocampus for lorazepam but not for alprazolam. Substitution of alprazolam for lorazepam resulted in downregulation in cortex only, similar to lorazepam alone. Conversely, substitution of lorazepam for alprazolam led to binding changes similar to lorazepam alone. These data demonstrate cross-tolerance to the convulsant effects of pentylenetetrazole between lorazepam and alprazolam. However, effects of the two compounds on benzodiazepine receptor binding in hippocampus remain distinct.

Chronic administration of benzodiazepine active at the tau-aminobutyric acidA receptor ("central" benzodiazepine sites) is associated with behavioral tolerance and receptor downregulation. Recent reports indicate possible interactions between central sites and benzodiazepines active at "peripheral-type" sites located primarily on non-neuronal cells. To evaluate these interactions during chronic administration, we treated mice with lorazepam for 1 to 14 days alone or in combination with the peripheral-type site ligand PK11195 [N-methyl-N-(methyl-1-propyl)chloro-2-phenyl-1-isoquinoline-3-carboxamid e]. Lorazepam was associated with tolerance at 7 days, but tolerance was not observed during concurrent administration of PK11195. Lorazepam was also associated with benzodiazepine receptor down-regulation in cortex and hippocampus at 7 days. With concurrent administration of PK11195, this effect remained in cortex but was absent in hippocampus. tau-Aminobutyric acid-dependent chloride uptake was reduced in both cortex and hippocampus with lorazepam, but not with concurrent lorazepam and PK11195. PK11195 administration alone did not affect behavior or neurochemical parameters, or did it alter brain lorazepam concentrations. These data indicate that concurrent PK11195 administration attenuates behavioral and neurochemical effects of chronic lorazepam administration.

Prenatal benzodiazepine exposure has been associated with neurobehavioral alterations in humans and animals. To determine effects of prenatal benzodiazepine exposure on binding at the benzodiazepine and t-butylbicyclophosphorothionate (TBPS) sites on the GABAA receptor in mature offspring, we treated mice with lorazepam, 2 mg/kg/day, during days 13-20 of gestation. Binding was assessed at 6 weeks of age. There were no differences among controls, vehicle- or lorazepam-exposed mice in benzodiazepine receptor binding determined in vivo or in vitro. However, receptor density for [35S]TBPS binding sites was decreased in lorazepam-exposed offspring compared to the other groups. These data are consistent with prior neurochemical results indicating decreased TBPS binding and GABAA receptor function in several systems.

Prenatal exposure to benzodiazepines may lead to developmental abnormalities in humans and animals. To assess the behavioral and neurochemical effects of such exposure, pregnant mice were treated with lorazepam, 2 mg/kg/day, from days 13-20 of gestation, and open-field activity was assessed in offspring at 3 and 6 weeks of age and the function of GABAA receptors at 6 weeks of age. Activity was increased in mice exposed to lorazepam, compared to untreated or vehicle-treated controls at 3 weeks, but was unchanged at 6 weeks. Muscimol-stimulated uptake of chloride was decreased in lorazepam-treated mice, compared to controls, with a decrease in maximum uptake but no change in the EC50 for muscimol. Concentrations of lorazepam in maternal plasma and brain showed a similar brain:plasma ratio as previously reported and concentrations in fetal brain were about 50% of maternal levels. Lorazepam persisted for 48 hours after birth in dams but not in the offspring. These results indicate persistent behavioral and neurochemical alterations after prenatal exposure to lorazepam. This model may be useful in assessing other effects of prenatal exposure to benzodiazepine.

Benzodiazepine discontinuation can lead to a behavioral syndrome in animals and humans. In a mouse model, this syndrome is associated with benzodiazepine receptor up-regulation. The protein-modifying reagent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), has been used to irreversibly inactivate a number of neurotransmitter receptors including benzodiazepine receptors, and thus allows estimation of receptor recovery in vivo. To assess benzodiazepine receptor recovery after benzodiazepine discontinuation, we treated mice with lorazepam (LRZ), 2 mg.kg-1.day-1 for 1 wk. After 24 h, EEDQ (12.5 mg/kg) was administered, and benzodiazepine binding in the cortex and cerebellum was determined after 4-144 h. EEDQ treatment decreased receptor density in the cortex in both LRZ- and vehicle-treated groups by approximately 50%, with no change in apparent affinity as previously reported. Binding in both groups returned to control values after 96 h. Kinetic analysis indicated a more rapid increase in binding in LRZ-compared with vehicle-treated animals, with t1/2 for LRZ 19.1 h, and for vehicle, 30.8 h (P less than 0.05). Receptor density was decreased in the cerebellum after EEDQ by approximately 40% in both treatment groups, with no change in apparent affinity. Receptor density returned to control values at 96 h, with no difference in kinetics in LRZ- compared with vehicle-treated mice. The decrease in receptor t1/2 associated with lorazepam discontinuation is consistent with the observed increase in benzodiazepine receptors in this setting.

1. Chronic benzodiazepine administration has been associated with tolerance and with downregulation of gamma-aminobutyric acidA (GABAA)-receptor binding and function. However, effects of individual benzodiazepines on brain regions have varied. 2. To compare the effects of chronic lorazepam and alprazolam, we have administered these drugs to mice for 1 and 7 days (2 mg kg-1 day-1) and determined benzodiazepine receptor binding in vivo with and without administration of CL 218,872, 25 mg kg-1 i.p., and GABA-dependent chloride uptake in 3 brain regions at these time points. 3. Benzodiazepine binding was decreased in the cortex and hippocampus at day 7 compared to day 1 of lorazepam, with an increase in CL 218,872-resistant (Type 2) sites in both regions. Maximal GABA-dependent chloride uptake was also decreased in the cortex and hippocampus at day 7. 4. Binding was decreased only in the cortex after 7 days of alprazolam, with no significant change in Type 2 binding. Maximal GABA-dependent chloride uptake was also decreased only in the cortex. 5. These data suggest that the effects of chronic benzodiazepine administration on the GABAA-receptor may be both region-specific and receptor subtype-specific.

Four healthy male volunteers received 5 mg lorazepam as a single intravenous injection. Concentrations of lorazepam and its glucuronide metabolite were determined in multiple venous blood samples drawn during the 48 hours after dosing and in all urine collected during 96 hours after the dose. Mean pharmacokinetic parameters for lorazepam were: apparent elimination half-life, 13.2 hours; volume of distribution, 0.84 liter/kg; total clearance, 55.3 ml/min. Lorazepam glucuronide, the major metabolic product of lorazepam, promptly appeared in blood, reached peak levels within 6 hours of the dose, then declined in parallel with the parent compound. A mean of 69 per cent of the dose was recovered in urine as lorazepam glucuronide.

The authors describe three patients who attempted to commit suicide by ingesting overdoses of lorazepam, an intermediate-acting benzodiazepine that, unlike diazepam, has no active metabolites. All three patients were clinically well within 24-30 hours of ingestion, although high lorazepam concentrations persisted. The authors point out that the elimination half-life of lorazepam after extremely high doses have been ingested is approximately the same as that found after ingestion of usual therapeutic doses.

Eleven subjects received acetaminophen (650 mg i.v.) on two occasions in random sequence, with and without concurrent administration of probenecid (500 mg) every 6 hr. Nine subjects similarly received lorazepam (2 mg. i.v.) with and without concurrent probenecid. Acetaminophen half-life was prolonged during probenecid treatment (mean +/- S.E., 4.30 +/- 0.23 vs. 2.51 +/- 0.16 hr; P less than .001) due to markedly decreased clearance (178 +/- 13 vs. 329 +/- 24 ml/min; P less than .001) with no change in volume of distribution (65 +/- 4 vs. 69 +/- 3 l; NS). Urinary excretion of acetaminophen glucuronide during 24 hr was decreased (84 +/- 9 vs. 260 +/- 21 mg of acetaminophen as glucuronide; P less than .001) and acetaminophen sulfate excretion was increased (323 +/- 25 vs. 217 +/- 17 mg of acetaminophen as sulfate; P less than .005) during concurrent probenecid treatment. However, the sum of the two conjugated metabolites was not significantly different (407 +/- 28 vs. 476 +/- 20 mg of acetaminophen as glucuronide plus sulfate excreted per 24 hr; NS). Lorazepam half-life was also prolonged during probenecid treatment (33.0 +/- 3.9 vs. 14.3 +/- 1.08 hr; P less than .001) due to decreased clearance (44.7 +/- 5.4 vs. 80.3 +/- 13.2 ml/min; P less than .001) with no change in volume of distribution (111 +/- 5 vs. 111 +/- 7 l; NS). Formation of the ether glucuronides of acetaminophen and lorazepam is impaired markedly by therapeutic doses of probenecid. Sulfate conjugation is not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty-nine healthy volunteers received single oral doses of either alprazolam (1 mg), lorazepam (2 mg), prazepam (20 mg), or placebo in a randomized, double-blind, parallel group study. Plasma drug concentrations, subjective self-ratings, and the digit symbol substitution test (DSST) were evaluated during 24 hours after dosage. Alprazolam was absorbed rapidly and produced correspondingly rapid sedation and impaired DSST performance. These effects also resolved rapidly, being similar to placebo by 4 to 6 hours after dosage. Sedative and DSST-impairing effects of lorazepam were of slower onset but longer duration than those of alprazolam. After oral prazepam, appearance of desmethyldiazepam in plasma was slow, with minimal sedative and DSST-impairing effects. Twenty-four hours after dosage, both alprazolam and lorazepam significantly impaired recall of a list of 16 words learned previously 3 hours after dosage. Thus benzodiazepines with approximately equivalent clinical anxiolytic properties may have different sedative, performance-impairing, and amnesic profiles after single doses in healthy volunteers; these differences are explained at least in part by pharmacokinetic variations.

Fifteen healthy male volunteers received long-term daily treatment with oral lorazepam at doses as high as 10 mg per day for a period of 26 weeks. Steady-state plasma concentrations of lorazepam and its glucuronide metabolite were measured in all subjects at least every two weeks. At daily doses of 6 mg per day, the mean steady-state lorazepam level was 88 ng/ml and that of lorazepam glucuronide was 170 ng/ml. Mean levels among seven subjects who received 10 mg per day were 164 and 266 ng/ml, respectively. Lorazepam concentrations fluctuated from week to week despite constant dosage, but there was no evidence of systematic variation. Mean steady-state lorazepam levels were highly correlated with daily dose in mg/kg, but were not related to age. Lorazepam was not detected in any plasma samples drawn one week after discontinuation of treatment.

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 (t1/2beta) 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 less than 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 loraxepam was assessed in 10 of the elderly subjects. Deltoid IM 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 (t1/2a) 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.

Eight healthy male subjects received single 2-mg oral doses of lorazepam containing 24 muCi/mg of 2-14C-lorazepam. Multiple venous blood samples were drawn during the first 96 hr after the dose, and all urine and stool were collected for 120 hr after dosing. Concentrations of lorazepam and its metabolites in body fluids were determined by appropriate analytic techniques. Following a lag time, lorazepam was absorbed with an apparent first-order half-life of 15 min. The peak plasma concentration was 16.9 ng/ml, measured in the pooled sample drawn 2 hr after the dose, This corresponded to the time at which clinical effects appeared to be maximal. The apparent elimination half-life of lorazepam was about 12 hr. Biotransformation to a pharmacologically inactive glucuronide metabolite appeared to be the major mechanism of lorazepam clearance. A mean of 88% of administered radioactivity was recovered in urine, and 7% was recovered in stool. Lorazepam glucuronide comprised 86% of urinary reactivity; its renal clearance was 37 ml/min. Other identified metabolites included hydroxylorazepam, a quinazolinone derivative, and a quinazoline carboxylic acid; all of these were quantitatively minor.

Six healthy volunteers received a single i.v. dose of 'low dose' lorazepam (0.0225 mg/kg), 'high dose' lorazepam (0.045 mg/kg) and placebo by 1-min infusion in a double-blind three-way crossover study. Plasma concentrations were measured 24 hr after dosage, and the EEG power spectrum was simultaneously computed by fast-Fourier transform to determine the percentage of total EEG amplitude occurring in the 13-30-Hz range. Low and high dose lorazepam did not differ significantly in distribution volume (1.89 versus 1.81 l/kg) or elimination half-life (11.5 versus 12.2 hr); clearance was slightly although significantly reduced at the higher dose (2.08 versus 1.88 ml/min/kg, P less than .005). EEG effects were of relatively slow onset, reaching their maximum change over baseline 30 min after infusion. The duration of action was prolonged, with the fraction of EEG activity in the 13-30-Hz range still significantly above baseline 8 hr after the 0.045 mg/kg dose. Five of these subjects received 0.15 mg/kg of i.v. diazepam in a companion study of identical design. EEG effects of diazepam were shorter than those of lorazepam, probably because of the more rapid and extensive decline in plasma diazepam concentrations in the postinfusion distribution phase. In addition, the onset of diazepam's effect was immediate. In male CD-1 mice that received i.v. diazepam (8.3 mg/kg) or lorazepam (3.3 mg/kg), the brain:plasma concentration ratio was maximal 2.5 min after dosage for diazepam, but equilibration was delayed at least 30 min after dosage for lorazepam. Thus the slow onset of action of lorazepam is probably attributable to slow entry into brain.

Potential interactions of ranitidine with antipyrine, diazepam, and lorazepam were evaluated. Ten healthy male subjects were injected intravenously with antipyrine (1.2 gm), diazepam (10 mg), or lorazepam (2 mg) on two randomly assigned occasions, once in the otherwise drug-free state and once while concurrently taking a therapeutic ranitidine dose of 150 mg every 12 hr. Kinetic analysis for antipyrine showed no change in elimination t1/2 between trials (mean, 11.6 and 11.5 hr) with no change in volume of distribution (Vd) or total clearance (0.77 and 0.75 ml/min/kg). Diazepam analysis also showed unchanged t1/2 (32.3 and 28.9 hr) with no change in Vd or total clearance (0.42 and 0.39 ml/min/kg). Lorazepam as well had unchanged t1/2 (11.7 and 11.3 hr), Vd, and total clearance (1.52 and 1.65 ml/min/kg). Therefore ranitidine, unlike cimetidine, has no effect on either human hepatic drug oxidation, as measured by antipyrine and diazepam clearance, or human drug conjugation, as measured by lorazepam clearance.

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.

Seven healthy subjects received oral placebo, 1.5 mg lorazepam, or 3.0 mg lorazepam in a single-dose, three-way crossover study. Plasma lorazepam concentrations and subjects' self-rated sedative effects were evaluated at multiple points during 24 hours after each dose. Information acquisition and recall was studied by use of a 16-item word list at 3 and 24 hours after dosing. Lorazepam plasma concentrations were proportional to dose. Self-rated sedation was maximal 2 to 3 hours after lorazepam dosing, persisted for 8 hours, and was dose dependent in intensity; no significant sedation occurred with placebo. At 3 hours after placebo dosing, subjects learned a mean 96% of words presented during six trials; this was reduced to 79% and 62% after lorazepam, 1.5 and 3.0 mg, respectively (F = 6.2; P less than 0.02). Twenty-four hours after placebo, subjects recalled 92% of words presented the previous day, then improved to 99% after six relearning trials. After 1.5 and 3.0 mg lorazepam, however, only 52% and 44% of words were initially recalled from the previous day. Thus single oral doses of lorazepam within the therapeutic range produce dose-dependent sedation and impairment of information acquisition and recall.

A "withdrawal" or "rebound" syndrome may follow the abrupt discontinuation of chronic treatment with benzodiazepines. To assess the neurochemical basis of this syndrome, mice were treated with lorazepam, 2 mg/kg/day for 7 days, a course which produces tolerance and downregulation of receptor binding and function. Behavioral studies indicated that open-field activity in lorazepam-treated mice was similar to controls at 1 day postlorazepam. Activity was increased at 4 days postlorazepam, and had returned to control levels by day 7. Benzodiazepine receptor binding as measured by specific uptake of [3H]Ro15-1788 in several brain regions returned to control levels by day 2 postbrazepam but had increased above controls at day 4 postlorazepam. Binding returned to control levels by day 7. Similar results were observed using [3H]flunitrazepam in membrane preparations. A similar time course was also observed for the maximum binding of the chloride channel ligand t-[35S]butylbicyclophosphorothionate during this period. The IC50 value for muscimol inhibition of t-butylbicyclophosphorothionate binding was decreased at day 4, suggesting increased coupling between gamma-aminobutyric acid and the chloride channel. Muscimol-stimulated [36Cl-] up-take in cortical synaptoneurosomes was increased at day 4 postlorazepam. These results indicate that the benzodiazepine discontinuation syndrome is associated with upregulation of receptor binding and function at the gamma-aminobutyric acidA receptor complex.

1. The effects of lorazepam discontinuation on responses to benzodiazepine agonists and antagonists were studied in mice. 2. The convulsant dose of pentylenetetrazol was decreased after an acute dose of lorazepam (0.5 mg kg-1) at 4 days after drug discontinuation, compared to 1 or 7 days after discontinuation or to vehicle treatment. 3. The percentage of mice undergoing convulsions after an acute dose of FG 7142 (40 mg kg-1) was increased at 4 days after lorazepam discontinuation, compared to 1 or 7 days after discontinuation or to vehicle treatment. 4. After an acute dose (0.5 mg kg-1), lorazepam concentrations in cortex tended to be greater in lorazepam-treated compared to vehicle-treated mice at 4 days after discontinuation compared to 1 and 7 days. 5. These data indicate a shift toward reduced agonist sensitivity and increased inverse agonist sensitivity in mice 4 days after lorazepam discontinuation.

The clinical pharmacokinetics of lorazepam, a 3-hydroxy, 1,4-benzodiazepine, indicate that it is rapidly and readily absorbed, reaching peak concentrations in the blood proportional to the dose approximately 2 hours after oral administration. Blood levels decline thereafter, with an elimination half-life of about 12 hrs. Conjugation with glucuronic acid to form inactive lorazepam glucuronide is the major metabolic pathway. Seventy (70) to 75% of the administered dose is excreted as the glucuronide conjugate in the urine. On multiple-dose regimens, steady state blood levels directly proportional to the daily dose occur within 2--3 days and are maintained after several months of continuous treatment. The active drug and the glucuronide conjugate are completely eliminated from the blood within 1 week following the last dose.

This paper describes a rapid and sensitive method for analysis of lorazepam and its glucuronide metabolite in plasma and urine following therapeutic doses of lorazepam in humans. After addition of the structurally related benzodiazepine derivative, oxazepam, as the internal standard, 1-ml samples of plasma or urine are extracted twice at neutral pH with benzene (containing 1.5% isoamyl alcohol). The combined extracts are evaporated to dryness, reconstituted, and subjected to gas chromatographic analysis using a 3% OV-17 column and an electron-capture detector. Lorazepam glucuronide in urine is similarly analyzed following enzymatic cleavage with Glusulase. The sensitivity limits are 1--3 ng of analyzed following enzymatic cleavage with Glusulase. The sensitivity limits are 1--3 ng of lorazepam per ml of original sample, and the variability of identical samples is 5% or less. The applicability of the method to pharmacokinetic studies of lorazepam is demonstrated.

The influence of obesity on the distribution or clearance of lorazepam and oxazepam, two benzodiazepines biotransformed by glucuronide conjugation, was studied in a series of obese subjects (mean weight 113 kg; mean percent IBW 179%) and healthy controls of normal body habitus matched for age and sex. Overweight subjects and controls received 2 to 3 mg of lorazepam intravenously or 30 mg of oxazepam orally. Absolute Vd in obese compared to control subjects was increased for both lorazepam (131 vs. 77 L, p less than 0.001) and oxazepam (97 vs. 38 L, p less than 0.001). When normalized to body weight, Vd/kg was similar for both drugs. Total metabolic clearance was similarly increased in the obese cohort for lorazepam (102 vs. 63 ml/min, p less than 0.005) and oxazepam (157 vs. 50 ml/min, p less than 0.001). Again, when normalized to body weight, clearance per kilogram was similar for both drugs. Since both Vd and clearance increased with body weight, elimination half-life (dependent on both Vd and clearance) was not significantly different in obese subjects (lorazepam 16.5 vs. 14.9 hr; oxazepam 7.7 vs. 8.9 hr). A random subgroup of obese and control subjects received a single intravenous dose of acetaminophen, also biotransformed by conjugation. Acetaminophen clearance was significantly correlated with that of lorazepam (r = 0.59, p less than 0.01) and oxazepam (r = 0.87, p less than 0.001), and clearance of LRZ and OXZ were similarly intercorrelated (r = 0.72, p less than 0.01). Thus obesity is associated with enhanced capacity for biotransformation of drugs via glucuronide conjugation. conjugating capacity increases in proportion to TBW and is consistent among drugs biotransformed by this mechanism.

Tolerance occurs to a number of the pharmacodynamic effects of benzodiazepines. To assess pharmacokinetic and neurochemical aspects of tolerance, lorazepam (LRZ) was administered chronically to mice via implantable osmotic pumps and rotarod ataxia, plasma and brain LRZ concentrations, benzodiazepine receptor binding in vivo and in vitro, chloride channel binding and muscimol-stimulated chloride uptake were examined in various brain regions over a 14-day period. Behavioral tolerance, indicated by diminished rotarod ataxia, developed at all doses examined (1, 2, 4 and 10 mg/kg/day), with little change occurring before day 4. The greatest decrease in rotarod ataxia occurred between days 4 and 7. Plasma and brain LRZ concentrations were proportional to dose and were constant over time at each dose, indicating that tolerance was not pharmacokinetic. Benzodiazepine receptor binding as determined by the specific uptake of [3H]Ro15-1788 decreased in cortex, hypothalamus and hippocampus primarily between days 4 and 7, with an approximately 50% decrement in each region by day 7. Receptor binding and rotarod ataxia in cortex were highly correlated at each dose. Apparent affinity in vivo at the receptor was unchanged in cortex, indicating that altered ligand uptake was due to decreased receptor number. Similar results were observed in membrane preparations. There was a small, nonsignificant decrease in chloride channel binding at day 7 compared to day 1. Muscimol-stimulated chloride uptake into cortical synaptoneurosomes was decreased at day 7 compared to day 1. Thus, downregulation of benzodiazepine receptor binding and of gamma-aminobutyric acidA receptor function is closely associated with behavioral tolerance to benzodiazepines.

Ten healthy volunteers received single 2-mg doses of lorazepam on five occasions in random sequence. Modes of administration were: A, intravenous injection; B, deltoid intramuscular injection; C, oral tablets in the fasting state; D, sublingual dosage of oral tablets in the fasting state; and E, sublingual dosage of specially formulated tablets in the fasting state. Kinetic variables were determined from multiple plasma lorazepam concentrations measured during 48 hr postdose. After intravenous lorazepam, mean (+/- SE) values were: elimination half-life (t 1/2 beta), 12.9 (+/- 0.8) hr; volume of distribution, 1.3 (+/- 0.07) liters/kg; total clearance, 1.21 (+/- 0.1) ml/min/kg. Absorption of intramuscular lorazepam was rapid. Peak plasma levels were reached at 1.15 hr after dosage, with absorption half-life averaging 14.2 (+/- 4.7) min. Absorption or oral and sublingual lorazepam tended to be less rapid than intramuscular injection, although differences were not significant. Times of peak concentration were 2.37, 2.35, and 2.25 hr postdose for trials C,D, and E, respectively; values of absorption half-life were 32.5, 28.5, and 28.7 min. Absolute systemic availability for trials B, C, D, and E averaged 95.9, 99.8, 94.1, and 98.2%, respectively; none of these differed significantly from 100%. Values of t1/2 beta were highly replicable within individuals regardless of the administration route. Thus, sublingual lorazepam is completely absorbed and is a suitable administration route in clinical practice.

Six healthy volunteers participated in single- and multiple-dose pharmacokinetic studies of oral lorazepam. Following single 4-mg oral doses, peak plasma lorazepam concentrations ranging from 40 to 70 ng/ml were reached within 3 hr of the dose. Values of absorption half-life averaged 25 min (range 10.3-42.7 min), and elimination half-life (t1/2 beta) averaged 14.2 hr (range 8.4-23.9 hr). During 15 consecutive days of 3 mg per day administered in divided doses, accumulation to the steady-state condition was complete within several days of the initiation of therapy. Values of accumulation half-life (mean 21.1 hr) were slightly longer than t1/2beta, and the two were not well correlated. Observed accumulation ratios (mean 1.88) were very close to those predicted from the single-dose study (mean 1.77), but the correlation between the two (r = 0.51) was not significant in the small sample size. "Washout" half-life values (mean 14.9 hr) were highly correlated with t1/2beta (r = 0.92). Clearance of a single intravenous dose of antipyrine determined prior to the multiple-dose lorazepam study (mean 0.86 ml/min/kg) was essentially identical to that determined after the study (mean 0.87 ml/ min/kg). Overall, the rate and extent of lorazepam accumulation during multiple dosage were reasonably well predicted by the single-dose kinetic study. However, accurate prediction for any specific individual was not always achieved. Stimulation or inhibition by lorazepam of its own clearance probably does not explain imprecise prediction, since single-dose t1/2beta and washout half-life values were essentially identical. Furthermore, chronic lorazepam exposure has no apparent effect on hepatic hydroxylation capacity as measured by clearance of exogenously administered antipyrine.

A single dose of 4 mg of lorazepam was injected into the deltoid muscles of six healthy male volunteers. Multiple venous blood samples were drawn during 48 hr after the dose and all urine was collected for 24 hr after the dose. Concentrations of lorazepam and its major metabolite, lorazepam glucuronide, were determined by electron-capture gas-liquid chromatography. Lorazepam was rapidly absorbed from the injection site, reaching peak concentrations within 3 hr. Mean pharmacokinetic pamrameters for unchanged lorazepam were: apparent absorption half-life: 21.2 min; elimination half-life: 13.6 hr; volume of distribution: 0.9 L/kg; total clearance: 58.2 ml/min. Lorazepam glucuronide rapidly appeared in plasma, reached peak concentrations within 12 hr of the dose, then was eliminated approximately in parallel with the parent drug. Within 24 hr a mean of 47.6% of the dose was recovered in the urine as lorazepam glucuronide and less than 0.5% was recovered as unchanged lorazepam.