Benzodiazepines distribution

Distribution of benzodiazepines in I-octanol - water system was investigated by a direct shake flask method at the presence of the compounds used in HPLC mobile phases the phosphate buffer with pH 6,87 (substances (I) - (II)), acetic and phosphate buffer, perchloric acid at pH 3 (substances (III) - (VI)). Concentrations of substances in an aqueous phase after distribution controlled by HPLC (chromatograph Hewlett Packard, column Nucleosil 100-5 C, mobile phase acetonitrile - phosphate buffer solution with pH 2,5, 30 70 (v/v)). 

Distribution of benzodiazepines in system micellar pseudophase - water was investigated in micellar solutions of sodium dodecylsulfate. The protonization constants of benzodiazepines were determined by the UV-spectophotometry. Values of protonization constants increase with increasing of sodium dodecylsulfate concentration. The binding constants of two protolytic forms of benzodiazepines with a micellar pseudo-phase and P, values were evaluated from obtained dependence. 

Although, by analogy with the opioids, one would expect there to be an endogenous ligand for the widely distributed benzodiazepine receptor, its existence remains uncertain and we must be alert to the possibility that any such ligand(s) could have either agonist or inverse agonist activity. 

A benzodiazepine template was also reported by researchers at GlaxoSmithKline [85]. The lead molecule GW405212, (40), was identified from a 1,296-member library of 1,4-benzodiazepines prepared on Tentagel beads and screened initially in pools of 30 against CHO cells expressing the human oxytocin receptor. It is a highly potent inhibitor of oxytocin binding with a K of 8nM [86]. However, all attempts to improve the pharmacokinetic properties of this molecule were unsuccessful. It appears that the functionality responsible for the oxytocin activity is distributed around the periphery... 

AUC, area under the plasma concentration cuive BZ, benzodiazepine Cl, clearance t, elimination half-life Vd, volume of distribution. Data from Benzodiazepines. Fads and Comparisons 4.0 Online. Wolters Kluwer Health, Inc. 2005, http //online.factsandcomparisons.com and Madabushi R, Frank B, DrewelowB, etal. Hyperforinin St. John s wort drug interactions. Fur J Gin Pharmacol 2006 62 225-233. 

Since the volume of distribution is increased, the elimination half-life of lipid-soluble drugs is increased. This affects for example medium- and long-acting benzodiazepines as well as i.e. verapamil that can accumulate in the body. 

Montpied P, Martin BM, Cottingham SL, Stubblefield BK, Ginns El, Paul SM. 1988. Regional distribution of the GABA /benzodiazepine receptor (a subunit) mRNA in rat brain. J Neurochem 51 1651-1654. 

The half-life of a benzodiazepine is not predictive either of its onset of action or of the therapeutic response of the patient. However, the rate of absorption and distribution within the body are important parameters in determining the pharmacod)mamic response. The period for maximal response to treatment may be as long as 6 weeks, and there is no evidence... 

The duration and degree of reversal of benzodiazepine effects are related to the dose and plasma concentrations of flumazenil. The onset of reversal is usually evident within 1 to 2 minutes after the injection is completed. Within 3 minutes, 80% response will be reached, with the peak effect occurring at 6 to 10 minutes. Pharmacokinetics After IV administration, flumazenil has an initial distribution half-life of 7 to 15 minutes and a terminal half-life of 41 to 79 minutes. Peak concentrations of flumazenil are proportional to dose, with an apparent initial volume of distribution of 0.5 L/kg. After redistribution the apparent volume of distribution ranges from 0.77 to 1.6 L/kg. Protein binding is approximately 50%. 

The distribution of the benzodiazepines from blood to tissues and back again is a dynamic process with considerable influence on the onset and duration of the therapeutic effects produced by these compounds. Those having greater lipid solubility tend to enter the central nervous system more rapidly and thus tend to produce their effects more quickly. Several of the benzodiazepines have therapeutic effects that are much shorter in duration than would be predicted based on their rates of metabolism and excretion redistribution away from the central nervous system is of primary importance in terminating their therapeutic effects. 

Extensive sleep studies have been conducted with a variety of sedative-hypnotic drugs, and all of these drugs appear to alter the normal distribution of rapid eye movement (REM) and non-REM sleep. Most of the older sedative-hypnotic agents markedly depress REM sleep. In contrast, when the benzodiazepines are used in appropriate doses, they depress REM sleep to a much smaller extent. As with treatment of anxiety, the choice... 

Another intriguing link between sleep and anxiety lies in the distribution of benzodiazepine receptors in the brain. Given their selective... 

The majority of benzodiazepines are highly bound to plasma proteins (85 to 95%) with apparent volumes of distribution ranging from 1 to 3 L/kg3 due to rapid removal from plasma to brain, lungs, and adipose tissue. 

The pharmacokinetic properties of the benzodiazepines in part determine their clinical use. In general, the drugs are well absorbed, widely distributed, and extensively metabolized, with many active metabolites. The rate of distribution of benzodiazepines within the body is different from that of other antiseizure drugs. Diazepam and lorazepam in particular are rapidly and extensively distributed to the tissues, with volumes of distribution between 1 L/kg and 3 L/kg. The onset of action is very rapid. Total body clearances of the parent drug and its metabolites are low, corresponding to half-lives of 20-40 hours. 

---