Plasma concentration of diazepam and N-desmethyldiazepam in children after a single rectal or intramuscular dose of diazepam

Summary The absorption of diazepam and N-desmethyldiazepam after administration of diazepam solution for parenteral injection per rectum and intramuscularly was studied in 9 children (ages 3–12 years). Rectal administration of diazepam 1 mg/kg led to rapid absorption with plasma levels of 270–320 ng/ml within 5 min, and peak levels of 600–1300 ng/ml 10–60 min after administration. The absorption was comparable to that after intramuscular administration. A second peak in plasma diazepam concentration 6–12 h after dosing was observed in 6 children, which may have been due to mobilization of diazepam from the gastrointestinal mucosa produced by feeding 4 h after administration of the drug. A slowly increasing plasma level of N-desmethyldiazepam was observed during the first 24 h after administration of diazepam.     

The concentrations of diazepam and its metabolites in the plasma after an acute and chronic administration

The plasma diazepam, N-demethyldiazepam, and free oxazepam concentrations were studied in 12 neurotic outpatients during subchronic use, in 14 outpatients after chronic use, and in 8 test subjects after an acute intravenous administration. There are several reasons for believing that diazepam may induce its own metabolism in man:

1. The decrease in diazepam and N-demethyldiazepam concentrations in the plasma after 1–6 weeks therapy.
2. Comparatively low plasma diazepam concentrations in patients who had taken diazepam for several months or years.
3. Much higher concentrations of N-demethyldiazepam, the main metabolite, after intravenously given diazepam in chronic users of diazepam as compared to controls.
4. The decrease in the ability to form N-demethyldiazepam after abstinence, when diazepam was administered intravenously to a chronic user of diazepam before and after the abstinence of the drug.

Diazepam should be administered in small doses and for short periods of time only, or intermittently.     

Biological effect and plasma concentrations of DDAVP after intranasal and peroral administration to humans

DDAVP was administered intranasally (20 micrograms) and perorally (100 and 200 micrograms) to 6 hydrated volunteers. Urine was collected and blood was sampled at intervals for the following 6 hr. In all experiments DDAVP induced a marked and long lasting antidiuretic response. Radioimmunoassay of DDAVP in blood samples made it possible to calculate bioavailability of DDAVP after the two forms of administration. Following intranasal application 11.3% of the dose appeared in the blood and the figures for oral administration was 0.7-1.0%. Based on analysis of the amount of DDAVP excreted in the urine the urinary clearance rate was estimated to be 0.10 ml/min/kg body wt.     

Biopharmaceutics of rectal administration of drugs in man IX. Comparative biopharmaceutics of diazepam after single rectal,oral, intramuscular and intravenous administration in man

Rectal absorption of diazepam was studied in man and compared with intravenous, intramuscular and oral administration. Plasma concentrations of diazeparn were measured by means of HPLC analysis after a single dose of 10 mg diazeparn in a cross-over study in 9 healthy volunteers.Plasma concentration—time curves following intravenous administration were described by a tri-exponential function consistent with a three-compartment model system. It was calculated that the drug will not exhibit measurable first pass metabolism.Comparing the absorption rate constants it appeared that rectal absorption of a solution of diazeparn proceeded significantly (I <0.05) more rapidly than absorption after oral and intramuscular administration. Absorption from a macrogol suppository dosage form was rather slow.The mechanism of the rapid rectal absorption of diazeparn from the solute state was discussed. No essential difference in bioavailability was observed between the intramuscular injection, rectal solution and tablets as compared with the intravenous injection. Only for the suppository dosage form was bioavailability calculated to be significantly lower.     

Correlation between pharmacological effects and plasma cocaine concentrations after smoked administration

The relationship between blood cocaine concentrations and pharmacological effects is of both theoretical and practical interest. This study utilized a computer-assisted smoking device for the delivery of three active doses (10, 20, and 40 mg) of cocaine base to seven human volunteers. Doses were administered in an ascending dose design with random placement of placebo. Physiological, subjective, and performance measures were collected concurrently with blood samples. Mean peak plasma cocaine concentrations were achieved at 2 min after the 20-mg and 40-mg doses and at 5 min after the 10-mg dose. Maximal responses in systolic and diastolic blood pressure, "feel", "good" drug, and drug "liking" subjective effects were also achieved immediately after drug administration. Pupil diameter and heart rate increases demonstrated a modest counter-clockwise hysteresis in relation to plasma cocaine concentrations shortly after dosing. Systolic and diastolic blood pressure, heart rate, and some subjective and performance measures of drug effect demonstrated a biphasic response after smoked cocaine. Initial increases above baseline levels were followed by an apparent compensatory decrease below baseline levels at a later time after smoked cocaine. Despite evidence of hysteresis and biphasic responses for some measures, linear correlation was obtained between mean plasma cocaine concentrations and several pharmacological effects over a period of 4 h after dosing. Several subjective and cardiovascular measures returned to baseline levels in the presence of detectable concentrations of cocaine.     

奎硫平及其代谢产物血药浓度与疗效、副作用的相关性

目的 探讨奎硫平及其代谢产物血药浓度与疗效、副作用的相关性。方法 对15例精神分裂症患者给予富马酸奎硫平治疗,剂量为400mg·d-1,疗程为3周。采用阳性症状量表(SAPS)、阴性症状量表(SANS)、简明精神病量表(BPRS)和不良反应量表(TESS)于治疗前和治疗1、2、3周末分别评定疗效和副作用。治疗第8 d晨服药前和服药后1.5 h分别采静脉血2 mL,高效液相色谱-质谱联用测定奎硫平及其代谢产物血药浓度。结果治疗结束时,SAPS、SANS和BPRS评分较治疗前均显著降低;BPRS减分率及SAPS减分率仅与奎硫平的稳态谷浓度均呈正相关;SANS减分率与峰、谷浓度均不相关。不良反应主要为一过性头昏和心动过速;TESS中的抗α1肾上腺素因子分值与奎硫平稳态峰浓度正相关,TESS总分值及其他因子分值与奎硫平及其代谢产物血药浓度不相关。结论 奎硫平治疗精神分裂症疗效好、起效快、耐受性好;监测奎硫平血药浓度对优化奎硫平临床疗效和预防药物不良反应具有重要意义。     

Correlation of saliva codeine concentrations with plasma concentrations after oral codeine administration.

A clinical study was designed to determine if there was a predictable relationship between saliva and plasma codeine concentrations. Drug-free volunteers (n = 17) were administered a 30-mg dose of liquid codeine phosphate. Plasma and saliva specimens were collected at various times for 24 h after administration. Plasma and saliva were analyzed for codeine and morphine by positive-ion chemical ionization gas chromatography-mass spectrometry. The plasma codeine concentrations peaked between 30 min and 2 h after administration and ranged from 19 to 74 ng/mL with a mean of 46 ng/mL. Despite decontamination procedures, elevated saliva codeine concentrations were detected at the early collection times because of contamination of the oral cavity from the liquid codeine. Codeine concentrations in the 15 min specimens ranged from 690 ng/mL to over 15,000 ng/mL. After the initial 2-h period, the mean codeine saliva concentrations declined at a rate similar to that observed in the plasma, but remained 3 to 4 times greater than the plasma concentrations. During the elimination phase, half-life estimates for codeine in plasma and saliva were found to be equivalent, 2.6 and 2.9 h, respectively. However, the area under the curve (AUC) estimate for codeine in saliva was 13 times greater than the plasma AUC. Contamination of the saliva resulted in elevated saliva/plasma (S/P) concentration ratios for the first 1 to 2 h after drug administration. Consequently, S/P ratios in specimens collected in the first 15 to 30 min ranged from 75 to 2580. However, after the absorption phase, a significant correlation between saliva and plasma concentrations was observed (r = 0.809, p < 0.05) and mean S/P ratios remained constant (mean = 3.7). Although small changes in saliva pH were predicted to produce profound changes in the S/P ratios for codeine, this was not observed in the current study. Therefore, saliva codeine concentrations could be used to estimate plasma concentrations through the use of the S/P ratio once the oral contamination has been eliminated. However, these estimates should be made cautiously. One must ensure that oral contamination is not a factor. Also, as with blood-drug concentrations, considerable intersubject variability was observed.     

Plasma mexiletine concentrations following combined oral and intramuscular administration

Summary Mexiletine in doses of 50, 100 and 400 mg was administered by intramuscular injection to a healthy subject and the resulting plasma concentrations were compared with those after 100 mg given intravenously. The bioavailability of mexiletine given by this route is complete and the kinetics are linear with dose. Plasma mexiletine concentrations resulting from 200 mg given orally with either two 4-ml intramuscular injections each containing 100 mg (Mexitil_® — for intravenous use) or one 2-ml intramuscular injection of an experimental preparation containing 200 mg were compared in 3 and 6 normal subjects respectively. Plasma levels within the therapeutic range of 0.75–2 µg/ml were attained at mean times of 28.7 and 42.5 min respectively. Apart from raised plasma creatine phosphokinase levels (as would be expected following an intramuscular injection) the tolerability of intramuscular mexiletine injections was satisfactory. Further studies in patients will be required to determine whether the combined oral and intramuscular administration of mexiletine is of value in acute myocardial infarction.     

Blood and brain concentrations of imipramine, clomipramine and their monomethylated metabolites after oral and intramuscular administration in rats.

Imipramine and clomipramine were administered to rats by the oral and intramuscular routes as single and multiple doses. The concentrations of both drugs and their active demethylated metabolites desipramine and desmethylclomipramine were measured in blood plasma, blood cells and brain. The concentrations of the metabolites were higher and the concentrations of the parent substances lower after oral than after parenteral administration, both in blood and in brain. In brain imipramine, despiramine and clomipramine during continuous treatment exceeded their plasma concentrations by six to ten times. The corresponding figure for desmethylclomipramine was 1-7. The extent of accumulation of the investigated substances in the brain was independent of the route of administration.     

The absorption,blood concentrations and excretion of pentazocine after oral,intramuscular or rectal administration to man

Blood concentrations, urinary excretion rates and faecal excretion of unchanged drug were measured after oral, intramuscular or rectal administration of pentazocine; Significant inter-subject variation was observed. Blood concentration-time curves are related to urinary excretion rates. Relative physiological availabilities by each route were determined.     

Serum morphine concentrations after buccal and intramuscular morphine administration.

1. This study compared serum concentrations of morphine after administration of a buccal tablet (25mg) with those after intramuscular injection (10mg). 2. Buccal morphine was administered to eleven healthy volunteers and intramuscular morphine was given to five preoperative surgical patients. Serum morphine concentrations were assayed by high performance liquid chromatography (h.p.l.c.) in samples taken up to 8 h after drug administration. 3. Mean maximum morphine concentrations were eight times lower after buccal administration than after intramuscular injection and occurred at a mean of 4 h later. Individual morphine concentration-time profiles showed marked interindividual variability after administration of the buccal tablet, consistent with considerable variation in tablet persistence time on the buccal mucosa.     

Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects

The pharmacokinetic properties of hydromorphone in healthy young male subjects were studied after i.v., peroral, and rectal administration. After i.v. administration the following pharmacokinetic parameters were found: elimination half-life 2.36 +/- 0.5 h, hepatic extraction ratio 0.51, apparent volume of distribution 2.9 +/- 1.3 L kg-1 and volume of central compartment 0.23 +/- 0.2 L kg-1. The absolute bioavailability after peroral administration was 50.7 +/- 29.8 per cent, and that after rectal administration was 33 +/- 22 per cent.     

Relationship between cerebral pharmacokinetics and anxiolytic activity of diazepam and its active metabolites after a single intra-peritoneal administration of diazepam in mice

The relationship between the cerebral pharmacokinetics of diazepam and its active metabolites (desmethyldiazepam, oxazepam) and the anxiolytic effect evaluated by the four-plates test and the light/dark test were investigated after a single intra-peritoneal injection of diazepam (1 mg/kg or 1.5 mg/kg). For up to 30 min after administration, the sedative effect interfered with the anxiolytic effect, thus the results of the anxiolytic effect were not interpretable. From 30 min to 60 min after administration, this interference disappeared, the cerebral level of benzodiazepines was stable (the brain elimination of diazepam was compensated for by the appearance of desmethyldiazepam followed by oxazepam) but the anxiolytic effect decreased dramatically in all the tests with diazepam 1 mg/kg or 1.5 mg/kg. The acute tolerance to benzodiazepines and the difference of affinity for subtypes of GABA(A) receptors between diazepam, desmethyldiazepam, oxazepam could explain this result.     

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

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

Systemic availability of ergotamine tartrate after oral,rectal and intramuscular administration

Summary Plasma ergotamine levels were measured in 33 volunteers (subgroups 11, 12 and 10) after a single dose of ergotamine administered by various routes. Ergotamine tartrate was given in doses normally used in the treatment of acute migraine — 2.0 mg orally, 2.0 mg combined with 100 mg caffeine rectally and 0.5 mg i. m. Plasma ergotamine concentrations were determined by radioimmunoassay. The highest and longest lasting levels were found after i. m. administration, the peak concentration being 1.94±0.34 (SEM) ng/ml at 1/2 h. The corresponding maximum concentrations after oral and rectal administration were 0.36±0.08 ng/ml at 2 h and 0.42±0.09 ng/ml at 1 h. In most of the subjects the plasma ergotamine level began to rise again at 24 to 48 h. The cause of the elevation is not known but it might favour possible accumulation of the drug. Absorption from suppositories was at least as good as after oral administration and the former route may therefore be advantageous for migraine patients in whom nausea and vomiting during an attack may prevent efficient oral medication.     

Blood and brain concentrations of imipramine,clomipramine and their monomethylated metabolites after oral and intramuscular administration in rats

Imipramine and clomipramine were administered to rats by the oral and intramuscular routes as single and multiple doses. The concentrations of both drugs and their active demethylated metabolites desipramine and desmethylclomipramine were measured in blood plasma, blood cells and brain. The concentrations of the metabolites were higher and the concentrations of the parent substances lower after oral than after parenteral administration, both in blood and in brain. In brain imipramine, desipramine and clomipramine during continuous treatment exceeded their plasma concentrations by six to ten times. The corresponding figure for desmethylclomipramine was 1·7. The extent of accumulation of the investigated substances in the brain was independent of the route of administration.