Effect of omeprazole and cimetidine on plasma diazepam levels

Summary The effects of steady state dosing with omeprazole and cimetidine on plasma diazepam levels have been studied in 12 healthy males. Single doses of diazepam (0.1 mg · kg⁻¹ i.v.) were administered after one week of treatment with omeprazole 20 mg once daily, cimetidine 400 mg b. d. or placebo, and the treatment was continued for a further 5 days. Blood was collected for 120 h after the dose of diazepam for the measurement of diazepam and its major metabolite desmethyl diazepam. The mean clearance of diazepam was decreased by 27% and 38% and its half-life was increased by 36% and 39% after omeprazole and cimetidine, respectively. Neither drug had any apparent effect on the volume of distribution of diazepam. Desmethyldiazepam appeared more slowly after both omeprazole and cimetidine. It is concluded that the decrease in diazepam clearance was associated with inhibition of hepatic metabolism both by omeprazole and cimetidine. However, since diazepam has a wide therapeutic range, it is unlikely that concomitant treatment with therapeutically recommended doses of either omeprazole or cimetidine will result in a clinically significant interaction with diazepam.     

Behavioural and pharmacokinetic studies in the monkey (Macaca mulatta) with diazepam, nordiazepam and related 1,4-benzodiazepines.

1. Behavioural activity (delayed differentiation and spatial delayed alternation) and pharmacokinetics of diazepam and its metabolites, N-desmethyldiazepam (nordiazepam), 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-desmethyldiazepam (oxazepam), and of dipotassium clorazepate (clorazepate), were studied in the monkey (Macaca mulatta). Diazepam and its metabolites (1.8 and 3.0 mg/kg) and clorazepate (2.6 and 4.3 mg/kg) were given by intraperitoneal injection. 2. Hydroxylation of diazepam (temazepam and oxazepam) led to a loss of, or a considerable reduction in, behavioural activity, whereas activity was preserved, though modified, by demethylation (nordiazepam). It was not possible to establish change in behaviour at specific time intervals after clorazepate, but combined performance data revealed an effect. 3. The maximum mean plasma concentrations of diazepam, temazepam, oxazepam and clorazepate were observed at 0.5 h, and the maximum mean plasma concentration of nordiazepam was observed at 1 hour. Plasma concentrations of nordiazepam were the highest and decreased monoexponentially. Plasma concenqrations of the other drugs declined rapidly at first but more slowly later, and these data were analysed as biexponential models. In the analysis for metabolites, nordiazepam reached measurable levels after the injection of diazepam and clorazepate. 4. It is suggested that differences in the effects of closely related benzodiazepines may not be due solely to their plasma pharmacokinetic properties, but may arise from differences in their intrinsic activity.     

Pharmacokinetics of diazepam and nordiazepam in the cat

The cat has been used extensively as an experimental model for studying the pharmacology of compounds that exhibit CNS activity including diazepam and nordiazepam. However, since little is known about the distribution and elimination of diazepam in this species, the pharmacokinetics of diazepam and nordiazepam were studied in the cat following intravenous doses of 5, 10, and 20 mg/kg of diazepam and 5 and 10 mg/kg of nordiazepam. The disappearance of diazepam and nordiazepam from blood was fitted with classical equations. Theoretical and trapezoidal areas under the curve (AUCth and AUCtr) were calculated. The volumes of distribution (Vd beta) were calculated as model-independent parameters for diazepam and nordiazepam. Intrinsic hepatic clearance, extraction ratio, and tissue binding parameters were also calculated for diazepam. From the observed data, it is apparent that the blood concentrations and the resulting areas under the curves are proportional to the dose of diazepam administered and that the pharmacokinetics of diazepam were linear over the dose range studied. In addition, nordiazepam formed after diazepam administration appeared to be proportional to the dose of diazepam administered. The terminal elimination rate constant of nordiazepam remained constant over the dose range studied. It appears that both diazepam and nordiazepam are highly bound to tissue. The total body clearance of diazepam (4.72 +/- 2.45 mL/min/kg) is approximately six times that of nordiazepam (0.85 +/- 0.25 mL/min/kg). Approximately 50% of an administered dose of diazepam was biotransformed to nordiazepam in the cat.     

甲状腺功能对地西泮及其代谢产物在大鼠体内代谢的影响

目的：研究甲状腺功能对地西泮及其代谢物的药代动力学影响。方法：采用HPLC技术，测定不同甲状腺功能状态时，大鼠血液中地西泮及其体内主要代谢产物去甲基地西泮的浓度。结果：甲亢组大鼠地西泮在体内消除加速，峰浓度下降，AUC减少，消除T1/2缩短。甲减组大鼠则消除减慢，峰浓度增高，AUC增大，消除孔。延长。而其主要代谢产物去甲地西泮的药动学参数则相反。结论：甲状腺功能提高时，大鼠对地西泮的代谢能力明显增加，消除加速；而甲腺功能降低则相反。     

Possible multiple transporters were involved in hepatobiliary excretion of antofloxacin in rats

1. The aim of the current study was to investigate the characteristics of biliary excretion of antofloxacin (ATFX) in rats. Rats received a bolus intravenous injection followed by a constant-rate infusion of ATFX. When plasma concentrations of ATFX reached steady state, cyclosporin A, erythromycin, probenecid, cimetidine and diclofenac were administered intravenously to the rats. Samples of blood and bile were collected and the concentrations of ATFX were measured and the corresponding pharmacokinetic parameters were estimated. 2. Biliary excretion of ATFX was observed in rats subjected to CCl(4)-induced experimental hepatic injury for 24 h (CCl(4)-EHI(24h)). Steady state concentrations of ATFX were attained at 60 min following infusion. 3. A slight increase in concentration of ATFX in plasma was observed after cyclosporin A, erythromycin, probenecid and cimetidine treatment. Significant increases in ATFX plasma levels were found in rats treated with diclofenac. Cyclosporin A, erythromycin, probenecid, cimetidine and diclofenac treatment significantly decreased the steady state biliary clearance of ATFX to 55, 68, 54, 53 and 56% of control values, respectively. 4. Cyclosprin A, probenecid, erythromycin and cimetidine also inhibited the biliary excretion of ATFX glucuronide. Significant decrease in the steady state biliary clearance of ATFX and its glucuronide was observed in CCl(4)-EHI(24h) rats. 5. These results indicate that multiple transporters are possibly involved in the biliary excretion of ATFX.     

Diazepam and N-desmethyldiazepam concentrations in saliva, plasma and CSF.

1 Salivary and plasma diazepam and nordiazepam concentrations were measured in 51 paired samples from four experimental situations. In seven of the patients CSF samples were estimated. 2 Correlation of 0.89 (P less than 0.001) was observed between salivary and plasma diazepam and 0.81 (P less than 0.001) between salivary and plasma nordiazepam. 3 Mean salivary diazepam was 1.6% (+/- 0.3%) of the plasma diazepam. It was found to vary markedly in an acute dosage study. Mean salivary nordiazepam was 2.9% (+/- 1%) of the plasma measure and was dependent on salivary flow rate. 4 CSF diazepam was in equilibrium with unbound plasma diazepam and salivary diazepam. 5 Mean protein binding of diazepam in vitro was 99.3% with no variations as a function of concentration. 6 The results suggest salivary diazepam and nordiazepam measures to be of value in epidemiological studies. However, they do not predict accurately the plasma total or unbound drug concentration from a salivary sample in an individual.     

GC-ECD法检测血浆中地西泮及去甲西泮

目的用GC-ECD法分析血浆中地西泮及其主要代谢物去甲西泮。方法血浆中加入内标去烃基氟西泮,调pH至10.8,用二氯甲烷-正己烷(7∶3)提取地西泮及去甲西泮,用GC-ECD法进行分析。结果检材中分析物的回收率80%以上,检出限5μg·L-1以下。结论该方法灵敏度高,可用于口服地西泮10mg人体24h内血浆的分析。     

Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects

OBJECTIVES: To investigate the pharmacokinetic and pharmacodynamic profile of dabigatran in healthy elderly subjects; to assess the intra- and interindividual variability of dabigatran pharmacokinetics in order to assess possible gender differences; and to assess the effect of pantoprazole coadministration on the bioavailability of dabigatran. STUDY DESIGN AND SETTING: Open-label, parallel-group, single-centre study, consisting of a baseline screening visit, 7-day treatment period and post-study examination visit. SUBJECTS AND INTERVENTION: 36 healthy elderly subjects (aged > or =65 years) with a body mass index of 18.5-29.9 kg/m(2). Subjects were randomized to receive dabigatran etexilate either with or without coadministration of pantoprazole. Dabigatran etexilate was administered as capsules at 150 mg twice daily over 6 days and once on the morning of day 7. Pantoprazole was administered at 40 mg twice daily, starting 2 days prior to dabigatran etexilate administration and ending on the morning of day 7. MAIN OUTCOME MEASURES: The primary pharmacokinetic measurements included the area under the plasma concentration-time curve at steady state (AUC(ss)), maximum (C(max,ss)) and minimum (C(min,ss)) plasma concentrations at steady state, terminal half-life (t((1/2))), time to reach C(max,ss) and renal clearance of dabigatran. The secondary pharmacokinetic parameters included the mean residence time, total oral clearance and volume of distribution. The pharmacodynamic parameters measured were the blood coagulation parameters ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT). RESULTS: With twice-daily administration of dabigatran etexilate, plasma concentrations of dabigatran reached steady state within 2-3 days, which is consistent with a t((1/2)) of 12-14 hours. The mean (SD) peak plasma concentrations on day 4 of treatment in male and female elderly subjects were 256 ng/mL (21.8) and 255 ng/mL (84.0), respectively. The peak plasma concentrations were reached after a median of 3 hours (range 2.0-4.0 hours). Coadministration with pantoprazole decreased the average bioavailability of dabigatran (the AUC(ss)) by 24% (day 4; 90% CI 7.4, 37.8) and 20% (day 7; 90% CI 5.2, 33.3). Intra- and interindividual pharmacokinetic variability in the overall population was low (<30% coefficient of variation), indicating that dabigatran has a predictable pharmacokinetic profile. Prolongation of the ECT and aPTT correlated with, and paralleled, the plasma concentration-time profile of dabigatran, which demonstrates a rapid onset of action without a time delay, and also illustrates the direct mode of action of the drug on thrombin in plasma. The ECT increased in direct proportion to the plasma concentration, and the aPTT displayed a linear relationship with the square root of the plasma concentration. The mean AUC(ss) was 3-19% higher in female subjects than in male subjects, which was likely due to gender differences in creatinine clearance. The safety profile of dabigatran was good, with and without pantoprazole coadministration. CONCLUSIONS: Dabigatran demonstrated reproducible and predictable pharmacokinetic and pharmacodynamic characteristics, together with a good safety profile, when administered to healthy elderly subjects. Minor gender differences were not considered clinically relevant. The effects of pantoprazole coadministration on the bioavailability of dabigatran were considered acceptable, and dose adjustment is not considered necessary.     

Possible multiple transporters were involved in hepatobiliary excretion of antofloxacin in rats

1. The aim of the current study was to investigate the characteristics of biliary excretion of antofloxacin (ATFX) in rats. Rats received a bolus intravenous injection followed by a constant-rate infusion of ATFX. When plasma concentrations of ATFX reached steady state, cyclosporin A, erythromycin, probenecid, cimetidine and diclofenac were administered intravenously to the rats. Samples of blood and bile were collected and the concentrations of ATFX were measured and the corresponding pharmacokinetic parameters were estimated.

2. Biliary excretion of ATFX was observed in rats subjected to CCl₄-induced experimental hepatic injury for 24?h (CCl₄–EHI_24h). Steady state concentrations of ATFX were attained at 60?min following infusion.

3. A slight increase in concentration of ATFX in plasma was observed after cyclosporin A, erythromycin, probenecid and cimetidine treatment. Significant increases in ATFX plasma levels were found in rats treated with diclofenac. Cyclosporin A, erythromycin, probenecid, cimetidine and diclofenac treatment significantly decreased the steady state biliary clearance of ATFX to 55, 68, 54, 53 and 56% of control values, respectively.

4. Cyclosprin A, probenecid, erythromycin and cimetidine also inhibited the biliary excretion of ATFX glucuronide. Significant decrease in the steady state biliary clearance of ATFX and its glucuronide was observed in CCl₄–EHI_24h rats.

5. These results indicate that multiple transporters are possibly involved in the biliary excretion of ATFX.     

Cimetidine-theophylline interaction: effects of age and cimetidine dose

Influences of cimetidine dose and age on the cimetidine-theophylline interaction were evaluated. Group Y consisted of nine young adults, aged 22-35 years, and Group O of nine elderly adults, aged 60-74 years. Each subject completed three study phases in this randomized crossover study. During Phase A, oral dosing of 5 mg/kg theophylline was followed by 14 serial blood samples drawn over 36 h. Phases B and C involved the same procedures, but with oral cimetidine treatment of either 200 or 300 mg every 6 h, respectively. Theophylline pharmacokinetic parameters for Group Y, Group O, and Groups Y + O were calculated. Analyses of variance (ANOVA) for crossover design were performed for each variable. Intragroup interphase ANOVA results were interpreted using multiple range tests (Tukey's Q). Comparisons between groups were performed using two-sided Student's t tests (alpha = 0.05). Within each phase, the area under the concentration-time curve (AUC), elimination half-life (t1/2 el), clearance (Clp), and volume of distribution (Vd) of theophylline for the elderly subjects were not significantly different from those of the younger adults. Mean changes in AUC, t1/2 el, and Clp between Phases A and B for both Groups Y and O were highly significant (29.2 vs. 40.4, 36.7 vs. 44.8, and 25.9 vs. 29.8%, respectively). Further significant changes in those parameters were associated with 1.2 g/day of cimetidine (Phase C). Alterations of theophylline pharmacokinetics by cimetidine appear to be dose-related and are of similar magnitude in elderly and young healthy adults.     

Interaction of diazepam with famotidine and cimetidine, two H2-receptor antagonists

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

A rapid HPLC procedure for the simultaneous determination of chloroquine, monodesethylchloroquine, diazepam, and nordiazepam in blood

Chloroquine, monodesethylchloroquine, diazepam, and nordiazepam levels are simultaneously determined in whole blood or plasma by HPLC. Papaverine is used as internal standard, and the analysis is performed after protein-binding hydrolysis, absorption on Extrelut, and elution with diethyl ether/methylene chloride (70:30 v/v). UV detection is used at 343 nm for 12 min, then changed to 242 nm. There are two mobile phases with two flow rates. The procedure requires 30 min, is reproducible, sensitive (8-10 ng/mL for chloroquine and its metabolite, 4 ng/mL for diazepam and nordiazepam), and selective, especially towards other antimalarial agents and drugs like adrenaline or barbiturates, which may be used in chloroquine poisoning therapy. It can be used for pharmacokinetic studies, therapeutic control, to establish the diagnosis and prognosis of a chloroquine poisoning, and to follow and optimize treatment.     

An assessment of the pharmacokinetics and pharmacodynamics of single doses of amlodipine in elderly normotensives.

This study characterizes the single dose pharmacokinetic characteristics of the dihydropyridine calcium antagonist drug amlodipine in a group of 16 elderly subjects, aged 65 to 86 years (8 M:8 F). The most notable pharmacokinetic features were a prolonged terminal elimination half life of 48 +/- 16 hours and a delayed tmax of 7.3 +/- 1.3 hours. Consistent with the time to achieve peak plasma drug concentrations, there was a modest but significant reduction in blood pressure at 6-8 hours after dosing. Comparison of these results with those of published data for young subjects indicate not only a greater degree of intersubject variability but also a longer half life in the elderly, suggestive of reduced drug clearance, which may lead to higher plasma drug concentrations particularly at steady state.     

Lack of interaction between nefazodone and cimetidine: a steady state pharmacokinetic study in humans.

The steady-state pharmacokinetic interaction between nefazodone and cimetidine was evaluated in a three-period crossover study consisting of three treatments of 1 week duration with a 1 week washout between treatments. The 18 healthy, male study subjects received: nefazodone hydrochloride 200 mg twice daily (every 12 h) for 6 days; cimetidine 300 mg four times daily for 6 days; and 200 mg nefazodone hydrochloride twice daily + 300 mg cimetidine four times daily for 6 days. On day 7 of each treatment, only the morning dose was administered. Serial blood samples were collected for pharmacokinetic analysis after drug administration on day 7 of each treatment; blood samples for trough levels (Cmin) to assess attainment of steady state, were also collected just prior to the morning doses on days 2-7 of each study period. Plasma samples were assayed for cimetidine, and nefazodone and its metabolites hydroxynefazodone and m-chlorophenylpiperazine by specific, validated h.p.l.c. methods. Statistical analyses of Cmin data indicated that, regardless of treatment, steady state was achieved for cimetidine by day 2 and for nefazodone and its metabolites by day 3 of multiple dosing, and that there were no significant differences in Cmin levels between treatments. When nefazodone and cimetidine were co-administered for 1 week, no change in steady-state pharmacokinetic parameters for cimetidine, nefazodone or hydroxynefazodone was observed compared with each drug dosed alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of Cimetidine on the Pharmacokinetics and Pharmacodynamics of Chlorpheniramine and Diphenhydramine in Rabbits

Purpose. The effects of concomitant administration of the H₂-receptor antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H₁-receptor antagonists chlorpheniramine and diphenhydramine were studied in rabbits. Methods. A single dose of chlorpheniramine 10 mg (Group A) or diphenhydramine 10 mg (Group B) was given intravenously on three different study days as follows: 2 weeks before cimetidine administration, after giving cimetidine 100 mg/kg intravenously every 12 hours for one week, and two weeks after discontinuing the cimetidine. Serum chlorpheniramine and diphenhydramine concentrations were measured by HPLC. Histamine H₁-blockade was assessed by measuring suppression of the histamine-induced wheals in the skin. Results. The chlorpheniramine and diphenhydramine terminal elimination half-life values and area under the curve values were significantly increased, and the systemic clearance rates were significantly decreased, during concomitant administration of cimetidine. For each H₁-receptor antagonist, pharmacokinetic parameters were similar before cimetidine was co-administered and two weeks after cimetidine was discontinued. Wheal suppression produced by chlorpheniramine or diphenhydramine was increased and prolonged when cimetidine was administered concomitantly. Conclusions. Any enhanced peripheral H₁-blockade observed could be attributed, at least in part, to a pharmacokinetic interaction.     

Alteration of pentoxifylline pharmacokinetics by cimetidine

Pentoxifylline, recently approved for the treatment of intermittent claudication, is hepatically cleared with a high degree of first-pass metabolism. Subsequently, the effect of cimetidine on pentoxifylline pharmacokinetics was studied in humans. Ten healthy subjects received, in random cross-over fashion, pentoxifylline 400 mg as a controlled-release tablet every 8 hours with and without cimetidine 300 mg four times a day for 7 days. Pentoxifylline and metabolite plasma concentrations over one dosing interval were measured on day 7 of each phase. The unavailability of an immediate-release pentoxifylline dosage form prevented a single dose trial. Cimetidine significantly increased (P less than .05) pentoxifylline area under the curve at steady state 26.2% from 675 +/- 97 (mean +/- SEM) to 852 +/- 108 ng. hr/mL. The average steady-state plasma concentration increased 27.4% from 84 +/- 12 to 107 +/- 14 ng/mL (P less than .05). Apparent oral clearance decreased 21.5% from 1309 +/- 304 to 1027 +/- 244 mL/min (P less than .02). Significant alterations in pentoxifylline metabolite concentrations were also observed. The results of this trial suggest cimetidine elevates pentoxifylline plasma concentrations, presumably by decreasing apparent oral clearance, although a reduction in total body clearance or an increase in gastric absorption could not be ruled out.     

Biliary Excretion of Diazepam and its Metabolites in Man

Abstract: Ten mg diazepam was given intravenously to 12 patients with a T-tube in the common bile duct after choledochotomy (Group I) and to 10 patients after cholecystectomy (Group II). The concentrations of diazepam, of its main metabolite, N-demethyldiazepam, and of free oxazepam in the plasma of both groups and the conjugated and free concentrations of diazepam, N-demethyldiazepam, and oxazepam in the bile in the Group I were measured by gas chromatography. In Group I significantly lower plasma diazepam concentrations were obtained as compared with Group II indicating an enterohepatic circulation of diazepam. There was no significant difference in the concentrations of N-demethyldiazepam in the plasma between the two groups. In Group I the patients had frequently more free oxazepam in their plasma than in Group II. The main conjugated metabolite in the bile was N-demethyldiazepam (about 74 %). Traces of diazepam were in the conjugated form, but no conjugated oxazepam was found in the human bile. The enterohepatic circulation of diazepam and its metabolites may be partly responsible for the prolonged effects of diazepam.     

Pharmacokinetics of CM 57755, a new histamine H2-receptor antagonist, after single oral doses in man

The plasma pharmacokinetics and urinary excretion of CM 57755, an H2-receptor antagonist, were studied after administration of single oral doses in a range between a 100 and 700 mg in human volunteers. Pharmacokinetic parameters were calculated model-independent. Absorption of CM 57755 was bimodal and the maximum plasma concentration was reached between 2 and 4 h after dosing. The drug was widely distributed with an apparent volume of distribution between 140 and 200 l. The plasma clearance was between 56 and 69 L/h. The plasma concentrations declined following a monoexponential function with an elimination half-life of 2 h. No modification in the plasma clearance or other pharmacokinetic parameters with these doses was observed. Therefore, a linear pharmacokinetic profile of CM 57755 was proposed. About 40% of the parent drug was unchanged in urine excreted over the 24 h. The drug was compared with cimetidine and ranitidine, the three compounds seemed to exhibit a consistent pharmacokinetic profile.     

Interaction between Erythromycin and the Benzodiazepines Diazepam and Flunitrazepam

Abstract: The effect of erythromycin on the pharmacokinetics and pharmacodynamics of diazepam and flunitrazepam was investigated in two randomized, double-blind, cross-over studies. Healthy volunteers ingested erythromycin for one week 500 mg t.i.d. On the 4th day they ingested a single 5 mg dose of diazepam (6 subjects, Study 1) or 1 mg dose of flunitrazepam (5 subjects, Study 2), respectively. Plasma drug concentrations and psychomotor effects were measured during 42 hr after the ingestion of diazepam or flunitrazepam. In Study 1 erythromycin increased the area under the diazepam plasma concentration-time curve [AUC (0-42 hr)] by 15% (P<0.05) and the concentration of diazepam in plasma at 42 hr by 63% (P<0.05). The median peak concentration (C_max) and the half-life (t_1/2) of diazepam were increased but they did not change significantly (P=0.17 and 0.12, respectively). Plasma N-desmethyldiazepam concentrations were slightly reduced during erythromycin treatment up to 8 hr (P<0.05). In Study 2 the AUC (0-42 hr) of flunitrazepam was increased by 25% (P<0.05) during the erythromycin treatment. The t_1/2 of flunitrazepam increased significantly (P<0.05), but the C_max remained unchanged. The psychomotor effects of diazepam or flunitrazepam were not changed significantly by erythromycin. These pharmacokinetic interactions can be explained by the reduced metabolic elimination of diazepam and flunitrazepam. The interactions of erythromycin with diazepam and flunitrazepam seem to be slight and of limited clinical significance only.     

Liquid chromatographic assay and pharmacokinetics of halazepam and its metabolite in humans

A reversed-phase high-performance liquid chromatographic method is described for simultaneous quantification of halazepam and its major active metabolite, nordiazepam, in plasma. The method uses a solid-phase extraction procedure to prepare plasma samples. After extraction, the methanolic extract is evaporated, and the residue is then reconstituted in a small volume of mobile phase (a 40:60, v/v, mixture of 0.02 M phosphate buffer, pH 4.0, and methanol) and chromatographed. The total chromatography time for a single sample is approximately 10 min. A sensitivity of 1 ng/mL for halazepam and nordiazepam is attained when 1 mL of plasma is extracted. Analytical recovery of halazepam and nordiazepam added to the plasma ranged from 89 to 96%. The maximum within-day and day-to-day coefficients of variation for each compound at the concentration range of 2 to 100 ng/mL were 8.7 and 10.3%, respectively. Suitability of the method was assessed in a preliminary pharmacokinetic study in which three subjects were given a single 20-mg oral dose of halazepam following an overnight fast. It appeared from our kinetic analysis that halazepam is a drug with a fairly rapid absorption phase that is followed by a slow elimination phase. Mean oral plasma clearance of halazepam was 24 L/h. The mean apparent elimination half-life of nordiazepam (45.22 h) is considerably longer than that of halazepam (21.15 h).