RESUMEN

Oxazepam is the major metabolite screened in urine samples for the evidence of the use of benzodiazepine drugs. The methods currently used, however, are laborious and time consuming. This paper proposes an oxazepam detection method based on its hydrolysis and cyclization--a reaction catalysed by cerium (IV) in an ortho-phosphoric acid-containing medium--to form 2-chloro-9(10H)-acridinone, a strongly fluorescent molecule. The variables involved in the hydrolysis and cyclization stages were optimised. Oxazepam was detectable in the 5-900 ng mL(-1) range, with a detection limit of 4.15 ng mL(-1) for k=3. The method was successfully used for the determination of oxazepam in urine samples collected at different times after the oral administration of Valium and Tranxilium.

Asunto(s)

RESUMEN

A very long half-life of paroxetine (195 h instead of the usual value of around 16 h) was measured after an overdose with 2 g paroxetine and 1 g clorazepate in a patient who was an extensive cytochrome P4502D6 metabolizer. The patient recovered well without any clinically significant complications. A consequence of the close monitoring of paroxetine levels in this patient was that it was decided not to reintroduce any other antidepressant despite her suicide attempt, until normal levels of paroxetine had been reached, which took over 1 month.

Asunto(s)

RESUMEN

Stedim 6 and Clearflex, two new polyethylene-lined materials for infusion bags, were studied for their compatibility with disodium clodronate, chlorpromazine and maprotiline hydrochlorides, diazepam, and clorazepate dipotassium salt, comparatively with borosilicate glass flasks and polyvinyl chloride bags. Diazepam, the only drug to exhibit a marked sorption in PVC bags (the loss reached 25% of the initial concentration after a contact duration of 72 h), showed lower sorption in Stedim 6 bags (loss about 11% under the same conditions) and none in Clearflex bags. No significant difference was observed between the infusion solutions used as vehicles of the drugs (5% dextrose and 0.9% sodium chloride isotonic solutions). The results are discussed in terms of lipophilicity of the drugs and crystallinity of the polymers.

Asunto(s)

RESUMEN

The disposition of clorazepate, a benzodiazepine anticonvulsant, was determined in dogs after administration of a single oral dose of clorazepate (2 mg/kg of body weight) and after oral administration of clorazepate (2 mg/kg, q 12 h) concurrently with phenobarbital (5 mg/kg, q 12 h) for 44 consecutive days. Serum concentrations of nordiazepam, the active metabolite of clorazepate, were measured. After a single oral dose of clorazepate, maximal nordiazepam concentrations ranged from 569.6 to 1,387.9 ng/ml (mean, 880.2 +/- 248.9 ng/ml) and were detected 16.8 to 131.4 minutes (mean, 85.2 +/- 36 minutes) after dosing. After administration of phenobarbital for 44 consecutive days, maximal nordiazepam concentrations were significantly (P < 0.01) lower, ranging from 209.6 to 698.5 ng/ml (mean, 399.3 +/- 155.6 ng/ml) at 68.4 to 145.8 minutes (mean, 93 +/- 25.8 minutes) after dosing. Mean area under the curve (AUC) on day 1 (mean, 3.37 +/- 0.598 ng.min/ml) was significantly (P < 0.001) greater than AUC on day 44 (1.66 +/- 0.308 ng.min/ml). Oral clearance was significantly (P < 0.01) greater on day 44 (12.44 +/- 2.55 ml/min/kg), compared with that on day 1 (6.16 +/- 1.35 ml/min/kg). Values for area under the first moment curve, oral volume of distribution, mean residence time, and elimination half-life were not significantly altered by concurrent administration of phenobarbital. Administration of phenobarbital altered the disposition of clorazepate such that the amount of nordiazepam in circulation during each dose interval was significantly reduced. Adequate control of seizures in epileptic dogs, therefore, may require higher dosages of clorazepate when it is coadministered with phenobarbital.

Asunto(s)

Asunto(s)

RESUMEN

This review underlines the importance of considering in the overall evaluation of drug effect and efficacy not only the kinetics and activities of the administered drug, but also those of the chemical species (metabolites) which are formed in the body. The circumstances in which a role for active drug metabolites may be suspected are described, and a number of specific examples are given. Four different categories are described: drugs which are inactive precursors of active metabolites (e.g. DOPA and cyclophosphamide); active metabolites which contribute to the duration of action of the parent compound (e.g. hexamethylmelamine and clobazam); active metabolites showing a mechanism of action different from that of the parent compound (e.g. buspirone and 1-pyrimidinyl piperazine; fenfluramine and norfenfluramine); and active metabolites showing an antagonistic effect on the activity of the parent drug (e.g. trazodone and m-chlorophenyl-piperazine; aspirin and salicylate).

Asunto(s)

RESUMEN

Dipotassium chlorazepate (DPC) and diazepam (DZM) were given i.m. and i.v. to 6 healthy volunteers in doses of 20 mg (48.9 mumol) DPC and 15 mg (52.0 mumol) DZM. The interval between the injections was at least 1 week. Plasma samples were analyzed for DPC and DZM by HPLC. The bioavailability of DPC and DZM after i.m. administration, determined from computer calculated AUCs, was 1.04 and 0.85, respectively.

Asunto(s)

RESUMEN

Twelve healthy volunteers received a single 40-mg oral dose of the benzodiazepine derivative oxazolam, which serves primarily as a precursor of the active substance desmethyldiazepam (DMDZ). Concentrations of DMDZ were measured in multiple serum samples drawn for up to two weeks after the dose. Peak serum DMDZ concentrations averaged 115 ng/ml, measured at 8.6 hours after dosage. Mean DMDZ elimination half-life averaged 61 hours. Three of the subjects also received 40 mg each of prazepam and clorazepate, two other DMDZ precursors, on separate occasions. Although DMDZ elimination half-life was similar, total area under the curve (AUC) for DMDZ was larger for clorazepate, known to be completely transformed into DMDZ, than for oxazolam or prazepam the extent of whose conversion to DMDZ has not been previously established. After correcting for the different molar equivalent of DMDZ available from each preparation, the DMDZ ratio averaged 0.22 for oxazolam vs. clorazepate and 0.51 for prazepam vs. clorazepate. Thus, both oxazolam and prazepam lead to slow appearance of DMDZ in the systemic circulation. Furthermore the extent of DMDZ formation from oxazolam and prazepam is either incomplete or the drugs are incompletely absorbed. Equivalent doses of oxazolam, prazepam, and clorazepate should not be interchanged in clinical practice.

Asunto(s)

Asunto(s)

RESUMEN

Cimetidine (CIM) was used as an interacting agent on the disposition in dogs of dipotassium clorazepate ( CZP ) and its main metabolite nordiazepam (ND) in order to study some of the factors contributing to pharmacokinetic interspecies variation of benzodiazepines in dogs and man. A 0.5 mg/kg of body weight intravenous (i.v.) bolus dose of CZP was administered to 12 anesthetized mongrel dogs, 6 of them receiving also, 30 min before, a 1 mg/kg i.v. bolus dose of CIM followed by a constant i.v. infusion (1 mg/kg/hr) of CIM. Plasma ND and CZP concentrations were measured as a function of time with an high-performance liquid chromatography method. Plasma levels of CZP declined mono- and biexponentially in 1 and 5 dogs, respectively, for each group of animals. No statistically significant difference was found between CZP pharmacokinetic parameters when the 2 groups of dogs were compared. However, a 37% decrease in ND beta half-life, t1/2 beta, when CZP was associated with CIM, was found to be statistically significant. The i.v. administration of pure ND in two dogs, has shown that ND declines biexponentially with a t1/2 beta similar to the one estimated after CZP dosing in control animals. The hepatic metabolism of ND was found to be flow-independent and restrictive. The data, along with previously reported CIM interactions, suggest that several factors, which would be species-dependent, must be responsible of CIM effect on other drugs.

Asunto(s)

Asunto(s)

RESUMEN

5 patients with chronic renal failure on maintenance hemodialysis and 5 healthy matched controls received single 20-mg intravenous doses of clorazepate dipotassium. Clearance of pharmacologically active unbound desmethyldiazepam was reduced in renal failure patients as opposed to controls, and free fraction in serum was greater. Since desmethyldiazepam distribution was reduced in renal patients, elimination half-life was actually shorter than in controls (36 vs. 57 h). In 10 dialysis patients receiving chronic diazepam treatment (5-15 mg/day), steady-state concentrations of diazepam (56 ng/ml) and desmethyldiazepam (77 ng/ml) were significantly lower than in age- and weight-matched controls receiving similar doses (189 and 216 ng/ml, respectively). However after correction for the higher free fractions of both compounds in renal patients as opposed to controls, steady-state concentrations of unbound drug were found to be similar between groups. Interpretation of kinetic variables and steady-state serum concentrations of extensively protein-bound drugs requires consideration of alterations in protein binding that may occur in disease states.

Asunto(s)

RESUMEN

A five-compartment open model was used to simulate the blood concentration profiles of diazepam and its metabolite, desmethyldiazepam, following single- and multiple-dose administrations of diazepam. The parameter estimates for diazepam were previously reported literature values. The parameters estimates for the metabolite were calculated from literature values of blood concentrations of desmethyldiazepam following the administration of clorazepate. The five-compartment open model suggests that approximately 50% of the administered diazepam is biotransformed to desmethyldiazepam, and that the elimination profile of the metabolite is not altered by the presence of the drug. The model may also be readily adapted to predict the concentrations of diazepam and desmethyldiazepam in cerebrospinal fluid following the administration of diazepam by simply correcting the blood or plasma concentrations of the drug and metabolite for the degree of plasma protein binding.

Asunto(s)

RESUMEN

A rapid and sensitive high-performance liquid chromatographic method is described for the quantitative analysis of dipotassium clorazepate (CZP) and its major metabolite nordiazepam (ND) in fresh human and dog plasma. The method consists of two separate selective ND extractions from a plasma sample without and with conversion of all the CZP to ND. For quantitation, diazepam (DZP) is used as the internal standard. The chromatographic phase utilized in a reversed-phase Hibar EC-RT analytical column prepacked with LiChrosolv RP-18 with a solvent system consisting of acetonitrile-0.05 M sodium acetate buffer, pH 5.0 (45:55). The UV absorbance is monitored at 225 nm using a variable-wavelength detector. The mean assay coefficient of variation over a concentration range of 20-400 ng per ml of plasma is less than 3% for the within-day precision. Recoveries of ND, DZP and CZP (as ND) are essentially quantitative at all levels investigated. The calibration curves of ND are rectilinear (r2 = 0.99) from the lower limit of sensitivity (2 ng/ml) to at least 2000 ng/ml in plasma. Applicability of the method to CZP and ND disposition studies in the anaesthetized mongrel dog is illustrated. When the two separate selective nordiazepam extractions from plasma cannot be performed immediately after blood sampling, an extrapolation kinetic method is suggested for the estimation of CZP concentration. In all previous in vivo studies, CZP has been determined only with gas-liquid chromatographic methods.

Asunto(s)

Asunto(s)

RESUMEN

Benzodiazepines (BZD) are lipophilic molecules, undissociated agents which easily penetrate membranes. Pharmacokinetics of BZD arises from these chemico-physical properties. Thus BZD show a rapid placental transfer with significant uptake of the drug, in both early and late pregnancy. The changes in the placental structures and in the circulation of the uterus during pregnancy are responsible in the greater placental passage in late pregnancy. After repeated doses in pregnant women, BZD tend to accumulate on the fetus, and the " flappy infant" syndrome may occur. The disposition of diazepam in women to the end of the pregnancy is altered. The terminal half-life is about twice as in non pregnant control, the distribution volume is increased but the total plasma clearance is not changed. In neonate child and particularly in premature infant, elimination of the BZD is slower in relation with immaturity of the hepatic enzymes systems metabolising drugs. BZD appear in human milk, but only high clinical doses might be expected to exert an effect on the nursing newborn. In the first trimester of pregnancy use of BZD has to be exceptional; the safety of these products in early pregnancy has not yet been definitively established. In the late pregnancy and at the parturition, there are more clear indications. Generally high single doses and repeated and prolonged administrations have to be avoided.

Asunto(s)

RESUMEN

Sixteen young (21-40 years) and nine elderly (65-78 years) volunteers received single intravenous doses of antipyrine on two occasions: once in the control state, and again while receiving therapeutic doses of cimetidine (300 mg every six hours). In the control state, antipyrine half-life was longer in elderly than in young subjects (16.4 vs 11.0 hours), and metabolic clearance lower (0.48 vs 0.72 ml/min/kg). However, coadministration of cimetidine prolonged antipyrine half-life to a similar extent in elderly and in young groups (150 and 153 per cent of control) and reduced metabolic clearance to a similar extent in both (79 vs 69 per cent of control) groups. Three young and six elderly volunteers received a single 15 mg oral dose of clorazepate, a precursor of desmethyldiazepam, with and without cimetidine. As in the case of antipyrine, cimetidine prolonged desmethyldiazepam half-life similarly in young and elderly groups (175 vs 164 per cent of control) and similarly reduced metabolic clearance (51 vs 65 per cent of control). The elderly population may already have an impaired capacity to oxidize drugs. This capacity is further impaired by coadministration of cimetidine.

Asunto(s)

RESUMEN

Desmethyldiazepam pharmacokinetics were determined after oral administration of its precursor, clorazepate, to 12 obese subjects (mean weight: 105.4 kg; mean percent ideal body weight: 170%) who were matched for age, sex, and smoking habits with 12 normal controls (66.5 kg; percent ideal body weight: 103.3%). After an overnight fast, a single 15-mg clorazepate capsule, equivalent to 10.3 mg of desmethyldiazepam, was administered. Multiple plasma samples drawn 10-42 days postdose were analyzed for desmethyldiazepam by electron-capture GLC. Obese subjects compared to controls had a prolonged desmethyldiazepam elimination half-life (t1/2) (154.1 hr versus 57.1 hr; p less than 0.005). Assuming quantitative conversion of clorazepate to desmethyldiazepam and 100% systemic availability, volume of distribution (Vd) was greatly increased in the obese (158.8 liters versus 63.3 liters; p less than 0.001). The value of Vd remained greater even after correction for body weight (1.52 liter/kg versus 0.94 liter/kg; p less than 0.005). However, clearance of desmethyldiazepam was not different between groups (13.2 ml/min in obese versus 13.4 ml/min in controls). The percent ideal body weight was highly correlated with Vd (r = 0.82), as was total body weight (r = 0.86). The value of t1/2 was correlated highly with Vd (r = 0.89) but only weakly with clearance (r = -0.38). Therefore, the large increase in the desmethyldiazepam t1/2 value seen in obese subjects is predominantly due to the disproportionate distribution of this lipid-soluble drug into body fat as opposed to lean tissue. The contribution of clearance to desmethyldiazepam t1/2 was of much less importance than was Vd in this obese study population.

Asunto(s)

Asunto(s)

RESUMEN

Knowledge of the pharmacokinetic properties of the benzodiazepines is playing an increasingly important role in their use during pregnancy, labour and lactation. All of the benzodiazepine derivatives are lipophilic, undissociated agents which readily penetrate membranes. Thus, they exhibit rapid placental transfer with significant fetal uptake of the drug. In the first trimester of pregnancy there is seldom a clear indication for the use of benzodiazepines. In late pregnancy and at parturition there may be more clear indications for their use. During delivery, the lowest effective dose should be used, since after high doses the so-called 'floppy infant syndrome' may occur, and the slow elimination of these agents by the newborn should be considered. Oxazepam, lorazepam, nitrazepam and, especially, flunitrazepam, appear to penetrate the human placenta more slowly than diazepam, but the clinical significance of this phenomenon remains uncertain. All of these derivatives appear in human milk, but only high clinical doses might be expected to exert a possible effect on the nursing newborn.

Asunto(s)