[Clinical pharmacology of pentazocine-diazepam anesthesia. 2. Protein binding and pharmacokinetics of diazepam (author's transl)].
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Anesthesia↗
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Disposition of aminopyrine, antipyrine, diazepam, and indocyanine green in patients with liver disease or on anticonvulsant drug therapy: diazepam breath test and correlations in drug elimination.
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Adult↗
The effect of a novel pentadecapeptide BPC 157 on development of tolerance and physical dependence following repeated administration of diazepam.
A novel gastric pentadecapeptide BPC 157 with different beneficial activities and anticonvulsant effect interacting with GABAergic system could improve diazepam efficacy coadministered (10 microg/kg, 10 ng/kg i.p.) with diazepam (5.0 mg/kg i.p.) twice daily for 10 days, since diazepam chronic medication would otherwise predispose for diazepam- tolerance/withdrawal development (shorter latency to convulsion after convulsant). In diazepam chronically treated mice, it attenuated diazepam tolerance (provoked by later acute administration of diazepam together with convulsant) and postponed physical dependence/withdrawal effects (provoked by later administration of isoniazid). In tolerance assay, at 42 h after the end of conditioning regimen, shorter preconvulsive latencies than in healthy (non-diazepam conditioned) mice following isoniazid (800 mg/kg i.p.) (as hallmark of tolerance) were observed if diazepam (5.0 mg/kg i.p.) was again given acutely to mice previously conditioned with diazepam alone (use of picrotoxin 3.0 mg/kg i.p., as convulsant, with acute application of diazepam in previously diazepam conditioned mice did not lead to tolerance hallmark). This was completely avoided in diazepam+BPC 157 10 microg or diazepam+BPC 157 10 ng chronically treated animals. In physical dependence assay (isoniazid challenge assessed at 6, 14, 42 and 72 h after conditioning medication), when compared to diazepam non-conditioned healthy mice, in diazepam conditioned mice residual anticonvulsive activity was not present already at the earliest post-conditioning interval (i.e., not different latency to isoniazid-convulsions), whereas shorter preconvulsive latencies (as physical dependence/withdrawal hallmark) were noted in diazepam conditioned mice following isoniazid challenge at 42 h and at 72 h after end of conditioning treatment. In diazepam+BPC 157 10 microg- conditioned mice, a residual anticonvulsive activity (i.e., longer latency to isoniazid convulsion) was noted at 6 h post-conditioning, whereas shorter preconvulsive latencies appeared only at 72 h-post-conditioning period. In conclusion, taken together these data (lack of tolerance development (tolerance studies), prolonged residual anticonvulsive activity, and postponed physical dependence/withdrawal hallmark in diazepam+BPC 157 chronically treated mice) with common benzodiazepines tolerance/withdrawal knowledge, it could be speculated that BPC 157 acts favoring the natural homeostasis of the GABA receptor complex as well as enhancing the GABAergic transmission, and having a mechanism at least partly different from those involved in diazepam tolerance/withdrawal, it may be likely used in further therapy of diazepam tolerance and withdrawal.
Amino Acid Sequence↗
Diazepam adsorption to infusion sets and plastic syringes.
The adsorption of diazepam to infusion sets and plastic syringes was studied. Infusion solutions consisting of diazepam injection (Valium) in glucose 5.5%, or diazepam emulsion in a lipid emulsion (Intralipid 10%) were infused through two different infusion sets (Transcodan L-74 and Cutter IL). It was found that, when an infusion solution with a low diazepam concentration (0.04 mg/ml) was infused slowly (4 ml/h), the diazepam adsorption was more than 80%. At a higher diazepam concentration (0.1 mg/ml) and increased infusion rate (20ml/h) the adsorption decreased. Diazepam injection in glucose 5.5% was adsorbed to a higher degree (40-75%) than diazepam emulsion in glucose 5.5% (15-35%). When diazepam emulsion was diluted with the lipid emulsion, no diazepam adsorption to the infusion set occurred at this concentration and infusion rate. No significant difference between the two infusion sets could be found. The miscibility of diazepam emulsion with glucose 5.5%, glucose 10%, or sodium chloride 0.9% was examined. Diazepam emulsion proved to be miscible with glucose 5.5% and glucose 10%, but sodium chloride should not be used to dilute diazepam emulsion. The effect on the diazepam concentration of storing diazepam injection and diazepam emulsion in plastic syringes for up to 4h was also studied. It was found that the diazepam concentration remained unchanged during this time.
Adsorption↗
Factors affecting the availability of diazepam stored in plastic bags and administered through intravenous sets.
Factors affecting the loss of diazepam from i.v. admixtures to flexible polyvinyl chloride (PVC) bags and to various administration sets were studied. Admixtures containing diazepam and 0.9% sodium chloride injection were stored for up to 550 hours in flexible PVC bags and in glass vials at various temperatures. Diazepam injection containing two different solvents was used. Initial diazepam concentrations in storage studies ranged from 25 to 100 micrograms/ml and pH ranged from 4.2 to 7.5. To determine availability of diazepam after infusion through administration sets, solutions (50 micrograms/ml) from glass containers were run through six different sets at 1 ml/min for seven hours. In storage studies, the difference in composition of the solvent was found to have only a slight effect on the rate and extent of diazepam loss. Diazepam loss was unaffected by pH. For admixtures stored in 1000-ml flexible PVC bags, the fractional loss of diazepam was greater at small volumes. The diazepam concentration of solutions in flexible PVC bags decreased more rapidly during infusion than during storage of the total original volume. The fraction of diazepam remaining in stored solutions was independent of the initial concentration, but the rate and extent of diazepam loss was greater at higher temperatures. Diazepam loss was dependent on length of flexible PVC tubing, and diazepam availability was greater with faster flow rates. In solutions infused through the polyolefin Tridilset, 100% of the diazepam remained. When storage of diazepam admixtures in PVC bags or administration through PVC tubing cannot be avoided, measures to minimize the rate and extent of diazepam loss include decreasing the temperature and the storage time and increasing the surface-area-to-volume ratio and the flow rate. Equations are presented for calculating the amount of diazepam delivered.
Adsorption↗
Polymorphism in diazepam metabolism in Wistar rats.
We observed variations in the metabolism of diazepam in Wistar rats. We studied these variations carefully, and found that the variations are dimorphic and about 17% of male rats of Wistar strain we examined showed two times higher diazepam metabolic activities in their liver microsomes than the rest of animals at the substrate concentrations less than 5 microM. We classified them as extensive metabolizer (EM) and poor metabolizer (PM) of diazepam. No sex difference was observed in the frequency of appearance of EM. Activities of the primary metabolic pathways of diazepam were examined to elucidate the cause of this polymorphism in male Wistar rats. No significant differences were observed in activities of neither diazepam 3-hydroxylation or N-desmethylation between EM and PM rats, while activity of diazepam p-hydroxylation was markedly (more than 200 times) higher in EM rats, indicating that this reaction is responsible for the polymorphism of diazepam metabolism in Wistar rats. We examined the expression levels of CYP2D1, which was reported to catalyze diazepam p-hydroxylation in Wistar rats to find no differences in the expression levels of CYP2D1 between EM and PM rats. The kinetic study on diazepam metabolism in male Wistar rats revealed that EM rats had markedly higher V(max) and smaller K(m) in diazepam p-hydroxylation than those of PM rats, indicating the presence of high affinity high capacity p-hydroxylase enzyme in EM rats. As a consequence, at low concentrations of diazepam, major pathways of diazepam metabolism were p-hydroxylation and 3-hydroxylation in male EM rats, while in male PM rats, 3-hydroxylation followed by N-desmethylation. Due to this kinetic nature of p-hydroxylase activity, EM rats had markedly higher total CL(int) of diazepam than that of PM rats. Polymorphism in diazepam metabolism in humans is well documented, but this is the first report revealing the presence of the polymorphism in diazepam metabolism in rats. The current results infer polymorphic expression of new diazepam p-hydroxylating enzyme with lower K(m) than CYP2D1 in EM Wistar rats.
Animals↗
Discrimination of ethanol and of diazepam: differential cross-tolerance.
These experiments tested the hypothesis that cross-tolerance between ethanol (EtOH) and diazepam would occur in a drug discrimination paradigm. One group of rats (n = 28) was trained to discriminate EtOH (1.0g/kg, i.p.) from vehicle; another group of rats (n = 10) was trained to discriminate diazepam (5.6mg/kg, i.p.) from vehicle. Subjects were trained using a two-lever choice procedure where food was delivered under a fixed-ratio 10 schedule of reinforcement. In rats trained to detect EtOH, both EtOH (0.1-1.78g/kg) and diazepam (0.32-10mg/kg) dose dependently substituted for EtOH. Chronic administration of EtOH (6.8g/kg/12h for 7 days) resulted in 3-fold tolerance to EtOH and 6-fold cross-tolerance to the ability of diazepam to substitute for EtOH; chronic administration of diazepam (20mg/kg/8h for 7 days) failed to confer cross-tolerance to EtOH nor did it produce tolerance to the ability of diazepam to substitute for EtOH. In rats trained to detect diazepam, diazepam (0.56-10mg/kg) but not EtOH (0.1-1.78g/kg) substituted for diazepam. Chronic administration of diazepam (20mg/kg/8h for 7 days) produced 3-fold tolerance to diazepam; in contrast, chronic administration of EtOH (6.8g/kg/12h for 7 days) failed to confer cross-tolerance to diazepam. The dissociation of the cross-substitution and cross-tolerance patterns between EtOH and diazepam suggests that the population of benzodiazepine receptors that mediates substitution of diazepam for EtOH differs from the population of benzodiazepine receptors that mediates substitution of diazepam for diazepam.
Journal Article↗
Labelling of diazepam-sensitive and -insensitive benzodiazepine receptors with [3H]tert-butyl-8-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]benzodiazepine 3-carboxylate (ZG-63).
A diazepam-insensitive subtype of benzodiazepine receptor has been identified in the cerebella of several species, including man. t-Butyl-8-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4] benzodiazepine 3-carboxylate (ZG-63) was recently described as a selective, high affinity ligand at diazepam-insensitive benzodiazepine receptors. This compound was tritiated, and its properties as a radioligand evaluated in rat brain membranes. Consistent with the high affinity and selectivity described for the non-radioactive form of this compound, saturation analyses of [3H]ZG-63 binding to cerebellar diazepam-insensitive and other, diazepam-sensitive benzodiazepine receptors revealed Kd values of 2.6 +/- 0.2 nM and 10.6 +/- 1.4 nM, respectively. The density (Bmax) of cerebellar diazepam-insensitive receptors labelled with [3H]ZG-63 was not significantly different from values obtained with the prototypical diazepam-insensitive receptor ligand [3H]Ro 15-4513, representing approximately 30% of total cerebellar benzodiazepine receptors. [3H]ZG-63 also labelled cortical diazepam-sensitive benzodiazepine receptors, with Bmax values that were not significantly different from those obtained with [3H]flunitrazepam. Diazepam-insensitive benzodiazepine receptors in rat cerebral cortex could be detected with [3H]ZG-63, but the densities of these sites are a very minor component (< or = 5%) of total benzodiazepine receptors. In the presence of GABA, [3H]ZG-63 behaved as a 'gamma-aminobutyric acid (GABA) -positive', 'GABA-negative', and 'GABA-neutral' ligand at cortical diazepam-sensitive receptors, cerebellar diazepam-sensitive receptors, and cerebellar diazepam-insensitive benzodiazepine receptors, respectively. This profile differs from the prototype diazepam-insensitive receptor ligand, [3H]Ro 15-4513. Competition studies demonstrated a very high correlation (r2 = 0.98; P < 0.002) between the potencies of a series of benzodiazepine receptor ligands to inhibit [3H]ZG-63 and [3H]Ro 15-4513 binding to cerebellar diazepam-insensitive receptors. The high affinity and selectivity of [3H]ZG-63 for diazepam-insensitive receptors (diazepam-insensitive/diazepam-sensitive ratio of approximately 0.25) together with a GABA-shift profile which differs from Ro 15-4513 suggests that this compound may be useful in elucidating the function(s) of this benzodiazepine receptor subtype.
Animals↗
Diazepam attenuation of somatostatin binding and effect of somatostatin on accumulation of inositol 1,4,5-trisphosphate in the rat frontoparietal cortex.
Numerous reports in both humans and animals have confirmed that benzodiazepines produce amnesia; however, mechanisms mediating this effect are not clear. In view of the important role of brain somatostatin (SRIF) in the cognitive function of rats, this study sought to determine if the benzodiazepine, diazepam, alters somatostatinergic system in the rat frontoparietal cortex. Intraperitoneal (i.p.) administration of diazepam (5 mg/kg/day) to male Wistar rats (200-250 g) for 3 or 7 days decreased the number of SRIF receptors (26 and 37%, respectively) in synaptosomes from the frontoparietal cortex, without influencing their apparent affinity. This decrease in the tracer binding was not attributable to a direct effect of diazepam on SRIF receptors, because no decrease of SRIF binding was induced by a large concentration of diazepam (10(-4) M) when the drug was added to a preparation of synaptosomes from frontoparietal cortex of untreated rats. To determine if the effect of diazepam on SRIF binding is related to the binding of diazepam to its recognition site on the GABA(A) receptor, a benzodiazepine antagonist, 2-phenylpyrazolo[3,4-c]quinolin-3(5H)-one (CGS 8216) was administered before the diazepam injection. Pretreatment with CGS 8216 (20 mg/kg/day, i.p.) blocked completely the diazepam-induced decrease in the number of SRIF receptors. CGS 8216 alone had no observable effect. The decrease in the number of 125I-Tyr11-SRIF receptor induced by diazepam was accompanied by a decrease in the effect of SRIF, after 15 seconds of stimulation, on inositol 1,4, 5-trisphosphate (IP3) mass accumulation in the rat frontoparietal cortex at 3 (64%) or 7 days (59%) after its administration. Diazepam alone had no observable effect on mass accumulation of IP3. After 14 days of daily diazepam injections, the levels of binding of 125I-Tyr11-SRIF in the frontoparietal cortex returned to control values, coinciding with the tolerance that develops to this benzodiazepine agonists when administered chronically. The decrease in IP3 levels was still observed after 14 days (57%) diazepam administration. Diazepam and CGS 8216 did not affect SRIF-like immunoreactivity levels in the frontoparietal cortex at the three time intervals studied (3, 7 or 14 days). The alteration of frontoparietal cortex SRIF receptor-effector system after 3 or 7 days of diazepam treatment suggests that somatostatinergic neurotransmission plays a role in the mechanism of diazepam action on memory.
Animals↗
Importance of CYP2D3 in polymorphism of diazepam p-hydroxylation in rats.
Diazepam was metabolized to three primary metabolites, 3-hydroxy-diazepam, N-desmethyl-diazepam, and p-hydroxy-diazepam. Our previous studies reported metabolic position-specific inter- or intrastrain differences in diazepam metabolism among Sprague-Dawley, Brown Norway, Dark Agouti, and Wistar rats. Especially, there were marked ( approximately 300 fold) inter- or intrastrain differences in diazepam p-hydroxylation activity at low concentration of substrate. In this study, we investigated the enzyme that catalyzes diazepam p-hydroxylation. The activity toward diazepam p-hydroxylation was inhibited by anti-cytochrome P450 2D (CYP2D) antibody, suggesting that this activity was catalyzed by CYP2D isoforms. Comparing the expression levels of the CYP2D subfamily in liver microsomes from various strains of rats using anti-CYP2D2 antibody, we found that there was a band of protein that was consistent with the phenotype of diazepam p-hydroxylation. N-terminal amino acid sequences of the specific protein exactly corresponded to those of CYP2D3, indicating that CYP2D3 might be involved in diazepam p-hydroxylation. Moreover, using rat CYP2D isoforms expressed in yeast, we tested CYP2Ds to catalyze diazepam p-hydroxylation. CYP2D1 and CYP2D2 practically did not participate in diazepam metabolism. On the other hand, diazepam p-hydroxylation was catalyzed by CYP2D3. CYP2D4 had high activity toward diazepam N-desmethylation, but not p-hydroxylation. In conclusion, the polymorphic expression of CYP2D3 caused the inter- or intrastrain differences in diazepam p-hydroxylation among rat strains or individuals.
Alcohol Oxidoreductases↗
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.
Animals↗
Abecarnil enhances recovery from diazepam tolerance.
Treatment with diazepam (25 mg/kg; p.o., twice-daily for 17 days) induced tolerance to the anticonvulsant effect of diazepam against bicuculline-induced convulsions in mice. Cross-tolerance was observed to the anticonvulsant action of clonazepam, imidazenil but not abecarnil. While substitution of clonazepam (12 mg/kg; p.o., twice-daily for 15 days) for diazepam did not affect tolerance to diazepam, substitution of imidazenil (17 mg/kg; p.o., twice-daily for 15 days) for diazepam significantly increased sensitivity to the anticonvulsant effect of diazepam, although tolerance was not abolished. Tolerance to diazepam progressively decreased either after suspension of diazepam administration or replacement treatment with abecarnil (20 mg/kg; p.o., twice-daily). Complete recovery of diazepam efficacy was detected after 8 and 15 days of administration of abecarnil and vehicle, respectively. Binding experiments using [3H]-flumazenil showed that Kd values did not differ among treatment groups. A significant decrease in Bmax (-42%) was observed in the cortex of diazepam-tolerant mice whether or not also treated with imidazenil and clonazepam. Conversely, chronically diazepam-treated mice, that further received abecarnil for either 8 or 15 days or vehicle for 15 days showed Bmax values similar to those of vehicle-treated mice never exposed to diazepam. Results suggest that repeated abecarnil administration to diazepam-tolerant mice can facilitate re-adaptation of receptors to the diazepam-free state. It is proposed that replacement therapy with abecarnil after long-term treatment with conventional benzodiazepines (BDZs) may provide a novel approach for reducing tolerance to their anticonvulsant effects.
Animals↗
Pharmacokinetics and anticonvulsant effects of diazepam in children with severe falciparum malaria and convulsions.
AIMS: Convulsions are a common complication of severe malaria in children and are associated with poor outcome. Diazepam is used to terminate convulsions but its pharmacokinetics and pharmacodynamics have not been studied in this group. Accordingly, we carried out a comparative study of the pharmacokinetics of intravenous (i.v.) and rectal (p.r.) diazepam. METHODS: Twenty-five children with severe malaria and a convulsion lasting >5 min were studied. Sixteen children received diazepam intravenously (i.v.; 0.3 mg kg(-1)) and nine rectally (p.r.; 0.5 mg kg(-1)). Plasma diazepam concentrations were measured by reversed phase high-performance liquid chromatography. The duration of convulsions, depth of coma, respiratory and cardiovascular parameters were monitored. RESULTS: Median maximum plasma diazepam concentrations of 634 (range 402-1507) ng ml(-1) and 423 (range 112-1953) ng ml(-1) were achieved at 5 and 25 min following i.v. and p.r. administration, respectively. All patients except three (one i.v. and two p.r.) achieved plasma diazepam concentration >200 ng ml(-1) within 5 min. Following p.r. administration, plasma diazepam concentrations were more variable than i.v. administration. A single dose of i.v. diazepam terminated convulsions in all children but in only 6/9 after p.r. administration. However, nine children treated with i.v. and all those treated with p.r. diazepam had a recurrence of convulsions occurring at median plasma diazepam concentrations of 157 (range: 67-169) and 172 (range: 74-393) ng ml(-1) , respectively. All the children in the i.v. and four in the PR diazepam group who had recurrence of convulsions required treatment. None of the children developed respiratory depression or hypotension. CONCLUSIONS: Administration of diazepam i.v. or p.r. resulted in achievement of therapeutic concentrations of diazepam rapidly, without significant cardio-respiratory adverse effects. However, following p.r. administration, diazepam did not terminate all convulsions and plasma drug concentrations were more variable.
Administration, Rectal↗
Diazepam in the treatment of organophosphorus ester pesticide poisoning.
Although the main site of action of diazepam, as with other benzodiazepines, is at the gamma-aminobutyric acid A (GABAA) receptor, the degree to which the beneficial actions of diazepam in organophosphorus (OP) ester pesticide poisoning are mediated through the GABAA receptor has been a matter of controversy. Although in most series of OP intoxications, convulsions have been relatively uncommon, it is probable that convulsions produce long-term sequelae in the central nervous system by causing structural damage. Animal studies have demonstrated that diazepam prevents and treats convulsions produced by OPs and may prevent the late effects caused by damage to the central nervous system induced by such convulsions. Consequently, the use of diazepam is an important part of the treatment regimen of severe OP poisoning as it prevents, or at least reduces the duration of, convulsions. In addition, case reports suggest that diazepam will also ameliorate muscle fasciculation, a subjectively unpleasant feature of OP pesticide poisoning. There are no data, either experimental or clinical, demonstrating any clear effect of diazepam alone on lethality in OP poisoning. In fact, in one study of large animals, diazepam, given alone, increased lethality. In animals experimentally poisoned with OPs, combined treatment with atropine and diazepam significantly lowered lethality compared with atropine treatment alone, indicating a clear beneficial effect. There are numerous case reports of the use of diazepam, generally as an adjunct to other more specific OP antidotes such as atropine and/or pyridinium oximes. Based on this evidence and pharmacodynamic studies in experimental animals, diazepam should be given to patients poisoned with OPs whenever convulsions or pronounced muscle fasciculation are present. In severe poisoning, diazepam administration should be considered even before these complications develop. Although diazepam has a large therapeutic index, there appears to be no place for its routine use in OP poisoning. Diazepam should be given intravenously to patients treated in hospital for OP poisoning, although the intramuscular route is used to administer diazepam outside hospital, such as on the battlefield, when an auto-injector is employed. It should be recognised, however, that absorption by the intramuscular route is poor.
Animals↗
Strain differences in diazepam metabolism at its three metabolic sites in sprague-dawley, brown norway, dark agouti, and wistar strain rats.
Knowledge of strain differences in drug metabolism is important for the selection of animals for pharmacokinetic, pharmacodynamic, and toxicological studies. Hepatic microsomes from Sprague-Dawley (SD) and Brown Norway (BN) rats had 300-fold higher diazepam p-hydroxylation activity than Dark Agouti (DA) and Wistar (W) rats at a low diazepam concentration (3 microM). Kinetic studies indicated that diazepam p-hydroxylation in SD and BN rats proceeded with lower K(m) and higher V(max) values than it did in DA and W rats. However, the expression levels of cytochrome P450 CYP2D1, the reported enzyme for diazepam p-hydroxylation, did not cosegregate with the activity. These results suggest the presence of a new high-affinity diazepam p-hydroxylation enzyme other than CYP2D1 in SD and BN rats. DA rats showed 3- and 2-fold higher diazepam 3-hydroxylation and N-desmethylation activities, respectively, than the other rat strains. In agreement with this, DA rat liver microsomes had a higher expression of CYP3A2, which is responsible for diazepam 3-hydroxylation and partly responsible for N-desmethylation. Values of CL(int) (V(max)/K(m)) indicated that p-hydroxy-diazepam is the major metabolite in SD and BN rats, whereas 3-hydroxy-diazepam is the major metabolite in DA and W rats. The sum of the CL(int) in each strain was in the order of DA > SD = BN >> W. Strain differences in the pharmacodynamics of diazepam between SD and DA rats may be due to these differences in diazepam metabolism. We found that both the rate of elimination of diazepam and the major metabolic pathways in diazepam metabolism differed among the different rat strains due to polymorphic expression of the two enzymes involved in diazepam metabolism.
Alcohol Oxidoreductases↗
Metabolism of diazepam and related benzodiazepines by human liver microsomes.
The metabolism of diazepam has been studied in vitro using microsomal preparations from five human livers. An HPLC method was developed for the assay of diazepam, its congeners and its metabolites. Various methods for the incorporation of diazepam into the incubation medium were explored. It was shown that the use of organic solvents or small quantities of hydrochloric acid enhanced the solubility of this substrate. However all of the organic solvents tested were associated with substantial (around 50%) inhibition of metabolism of diazepam by both major pathways (N-demethylation and C3-hydroxylation). The use of hydrochloric acid gave satisfactory solubilization of diazepam, but not of pinazepam, prazepam or halazepam. Detailed metabolic studies were conducted only for diazepam, using neither hydrochloric acid nor organic solvents in the incubation medium. Formation of N-desmethyl-diazepam increased approximately linearly with diazepam concentration to 200 microM, and did not show saturation. Formation of temazepam gave a curved profile over the same range of diazepam concentrations, suggestive of a sigmoidal relationship. Michaelis-Menten parameters could not be determined for either reaction, but intrinsic clearances for N-demethylation varied over a 6-fold range. Diazepam N-demethylation was apparently promoted by the inclusion of temazepam in the incubation medium, while C3-hydroxylation of diazepam was enhanced in the presence of N-desmethyldiazepam. Mephenytoin in the incubation mixture had no effect on diazepam metabolism by either pathway. The present studies have defined some of the methodological problems inherent in in vitro metabolic studies with benzodiazepines, and have shed further light on the metabolism of diazepam in vitro by human liver.
Adult↗
Benzodiazepines inhibit human platelet activation: comparison of the mechanism of antiplatelet actions of flurazepam and diazepam.
These studies were undertaken to examine the effects and the mechanism of action of flurazepam and diazepam on human platelet activation. One minute preincubation with flurazepam (3-300 microM) or diazepam (3-300 microM) inhibited platelet aggregation, serotonin secretion and prostaglandin synthesis induced by ADP (1-5 microM), epinephrine (1-5 microM), and arachidonic acid (600-1000 microM). However, 357% higher concentration of diazepam (265 microM) as compared to flurazepam (58 microM), was required to inhibit arachidonic acid induced production of malondialdehyde (MDA) by 50%. In addition, flurazepam and not diazepam inhibited the release of arachidonic acid from platelet phospholipids in a concentration dependent manner. In other experiments flurazepam but not diazepam also blocked aggregation and secretion induced by U46619 (2 microM), a stable analog of prostaglandin H2. Platelet aggregation and serotonin secretion induced by collagen (40-300 micrograms/ml) was inhibited by flurazepam with an IC-50 of 153 microM and 136 microM respectively, whereas higher than 300 microM diazepam was required to inhibit collagen-induced aggregation and secretion by 50%. Flurazepam and diazepam both exhibited their most potent antiplatelet effects against phospholipase C-induced aggregation which is mediated by prostaglandin-independent mechanisms. Only 15 microM and 11 microM flurazepam and 31 microM and 27 microM diazepam were needed to inhibit PLC-induced aggregation and secretion of serotonin by 50% respectively. Effects of these benzodiazepines on platelet cyclic AMP and cyclic GMP were also examined. Neither flurazepam nor diazepam caused any significant change in cyclic AMP or cyclic GMP levels in platelets. These findings suggest that: (a) flurazepam, as compared to diazepam, is 106% - 357% more effective in inhibiting platelet aggregation and serotonin secretion induced by arachidonic acid, collagen and phospholipase C; (b) flurazepam inhibits platelet activation by inhibiting the release of arachidonic acid, its conversion into prostaglandins and by blocking the action of prostaglandins on platelets; (c) diazepam does not inhibit thrombin-induced release of arachidonic acid, conversion of exogenously added arachidonic acid into MDA, or the action of prostaglandins; (d) both flurazepam and diazepam inhibit PLC-mediated activation of platelets; and (e) neither diazepam nor flurazepam achieve their antiplatelet actions by affecting platelet cyclic nucleotide levels.
Adenosine Diphosphate↗
Rectal diazepam for prehospital pediatric status epilepticus.
STUDY OBJECTIVES: To compare the feasibility, effectiveness, and safety of rectal diazepam and intravenous diazepam in the treatment of pediatric prehospital status epilepticus. DESIGN AND SETTING: Retrospective analysis of a 30-month consecutive sample of ambulance-transported children in a large urban emergency medical service region. TYPE OF PARTICIPANTS: Study group included 324 patients with seizure who were less than 18 years of age; 36 had status epilepticus, of whom 16 received rectal diazepam and 15 received IV diazepam. INTERVENTIONS: For children with status epilepticus, paramedics administered the 5-mg/mL IV solution of diazepam by one of two routes: rectally either through a 5F feeding tube with an attached syringe or by lubricated tuberculin syringe inserted 4 to 5 cm into the rectum at a one-time dose of 0.2 to 0.5 mg/kg or intravenously using a one-time dose of 0.1 to 0.3 mg/kg. Cardiopulmonary status was carefully monitored in the field and emergency department. MEASUREMENTS AND MAIN RESULTS: Thirteen of 16 children (81%) who received rectal diazepam stopped seizing after a single dose ranging from 0.16 to 0.57 mg/kg. Convulsions recurred before arrival at the ED in four of the 13 (30.8%). All of three patients who did not respond to rectal diazepam initially were 3 to 5 years old and had serious underlying comorbidity; two required endotracheal intubation in the ED and multiple anticonvulsants to terminate the seizure. No child treated with rectal diazepam required prehospital endotracheal intubation. All children who received IV diazepam stopped seizing after one dose ranging from 0.04 to 0.33 mg/kg. Convulsions recurred before arrival at the ED in nine of 15 children (60%); two required prehospital endotracheal intubation for profound respiratory depression. CONCLUSION: Rectal diazepam is a simple, effective, and safe method of prehospital management of pediatric status epilepticus. Compared with IV diazepam, rectal diazepam is easier to administer, especially in infants and toddlers; is equally efficacious; and is less likely to produce respiratory depression. Although respiratory depression is rare with rectal diazepam, prehospital personnel must be prepared to provide definitive respiratory support. Short duration of action is an important limitation of both treatments.
Administration, Rectal↗