Lipophilicity barbiturates

An alternative process that can lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excreted products. The role that metabolism plays in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates such as thiopental and pentobarbital would have extremely long half-lives if it were not for their metabolic conversion to more water-soluble compounds. 

Barbiturates are generally widely distributed throughout the body. The highly lipophilic barbiturates, especially those used to induce anesthesia, undergo redistribution when administered intravenously. Barbiturates enter less vascular tissues over time, such as muscle and adipose tissue, and this redistribution decreases concentrations in the blood and brain. With drugs such as thiopental, this redistribution results in patients waking up within 5 to 15 min after injection of a anesthetic dose. 

This is needed because of the mode of separation, with reversed-phase HPLC being based on a partitioning process. As the lipophilicity of the side-chain at the C5 position increases, so the barbiturate compound will partition preferentially into the stationary phase, but not re-enter the mobile phase. Increasing the proportion of acetonitrile in the solvent system will result in better mass transfer characteristics, and hence improved chromatography, for these more lipophilic barbiturates. 

The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Most of the barbiturates and other older sedative-hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral administration. 

Phenobarbital poisoning is exacerbated by its ionized forms also. Its pKa is about 7.2. At a urine pH of 7.4 there will exist about a 50 50 mixture of lipophilic and lipophobic species. Once again the uncharged form will be reabsorbed and the remaining barbiturate molecules will redistribute themselves according to the equilibrium eventually leading to the reabsorption of the virtually all of the phenobarbital. 

Comparing the lipophilicity of the barbiturates in Table 2.2 with their uptake across the GI tract (colon) demonstrates that the membrane permeability of each member of the series is proportional to its partition coefficient. Apparently, there can be some differential effect on partitioning depending upon which organic solvent is used in making the determination. For example, the GI membrane is believed to behave more like an octanol/water pairing, while drug uptake into the brain is more closely mimicked by a heptane/water combination. 

The effect of urinary pH on drug ionization also has toxicological implications. For example, in cases of phenobarbital (a weak acid barbiturate) overdose the urine can be alkalinized (the pH elevated) by administering sodium bicarbonate to the patient. The resultant increase in pH shifts the dissociation equilibrium for this weak acid to the right, producing an increase in the proportion of the ionized form, less reabsorption in the kidneys, and more rapid elimination. Conversely, acidifying the urine with ammonium chloride will increase the excretion rate of drugs that are weak bases since they will be more protonated (ionized) and less reabsorbed (more polar, less lipophilic). 

The utility of the highly soluble 6-cyclodextrin derivatives (soluble polymer and dimethyl-6-cyclodextrin) in RPTLC is illustrated in the separation of barbiturates. The lipophilicity of a barbiturate or any guest decreases when included in a cyclodextrin-cavity. Therefore its mobility is modified in reversed phase thin layer chromatography. With this simple and rapid method, the stability of a complex can be estimated empirically (Table II). The "b" value of the following equation is characteristic for the complex stability (in water ethanol =4 1 solution, R determined at 5 different cyclodextrin concentrations for 21 barbiturates) ... 

Such a system can be used to quantify barbiturates with relatively short alkyl substituents at the C5 position. The analytes will separate, eluting in order of lipophilicity, e.g. barbitone, butobarbitone, pentobarbitone, etc. However, as the substituents become increasingly apolar as the carbon chain-length increases, so the percentage of the acetonitrile in the mobile phase must also be increased. 

The basic principles behind the quantification of benzodiazepines are the same as those applicable to barbiturates. A typical set of HPLC operating conditions used for such analyses are shown in Table 9.5. Again, the compounds elute in order of increasing lipophilicity and, owing to the lack of any good chromophoric groups (cf. the barbiturates), a UV detection wavelength of 240 nm is also used for such materials. 

A relationship between the lipophilicity of the solubilisate, expressed by the partition coefficient between octanol and water, Poctanoi (see Chapter 5), and its extent of solubilisation has been noted for the soluhilisation of substituted barbituric acids by polyoxyethylene stearates, of substituted benzoic acids by polysorbate 20, and of several steroids by polyoxyethylene nonionic surfactants. An exhaustive survey of data for the solubilisation of some 64 dmgs by bile salt micelles revealed linear relationships between log (partition coefficient between micelles and water) and log Poctanoi ach of seven bile salts... 

In general, structural changes in the barbiturate series (see Chapter I4 that favor partitioning into the lipid tissue stores decrease duration of action but increase central nervous system (CNS) depres.sion. Conversely, the barbiturates with the slowest onset of action and longest duration of action contain the more polar side chains. This latter group of barbiturates both enters and leaves the CN.S more slowly than the more lipophilic thiopental. 

GABA. Dihydrovaltrate, hydroxyvalerenic acid, a hydroalcoholic extract containing 0.8% valerenic acid a lipid extract an aqueous extract of the hydroalcoholic extract, and another aqueous extract of V. officinalis (L.) were assessed for in vitro binding to rat GABA, benzodiazepine, and barbiturate receptors (18). The results indicated that an interaction of some component of the hydroalcoholic extract, the aqueous extract derived from the hydroalcoholic extract, and the other aqueous extract had affinity for the GABAa receptor. Because hydroxyvalerenic acid (a volatile oil sesquiterpene) and dihydrovaltrate (a valepotriate) did not show any notable activity, the investigators could not identify the specific constituents responsible for this activity. The lipophilic extract derived from the hydroalcoholic extract, as well as dihydrovaltrate, showed affinity for barbiturate receptors, and some affinity for peripheral benzodiazepine receptors. 

Distribution. The lipid solubility (lipophilicity) of barbiturates varies and determines how readily they cross the blood-brain barrier. 

Metabolism. The principal site of metabolic inactivation is in the liver. In the metabolism, the lipophilic character of the barbiturates decreases, which in turn decreases the ability of the barbiturates to penetrate into the CNS. There are four pri-... 

Barbiturates. QSAR studies by Hansch presented evidence that the hypnotic activity of barbiturates depends largely on their relative lipophilic character as determined by octanol-water partition coefficients (102-104). Employing Equation 5.6, a QSAR analysis was conducted on over 100 barbiturates as well as a number of non-barbiturates having hypnotic activity. 

Rg = H or CH, Rg = Et, R4 = Ph), which have pifa in the range of 7-8 and are 40-60% dissociated, are capable of crossing the blood-brain barrier and exertingCNS effeets, including sedation. It was shown that the ionized form of barbiturates can permeate liposomal bilayers provided that 5-substituents impart sufficient lipophilicity (157). 

Molecular volumes540 and fragmental constants541 of 5,5-substituents were used by Testa for elegant multiparameter correlations of the affinity for cytochrome P-450 and the hepatic clearance of 32 barbiturates.232 The results showed that the factors controlling these processes were lipophilic and steric in nature only the first effect was anticipated from the same metabolic data analyzed by the single parameter correlation.523... 

Since the lipophilic character was found important for physiological dispositions of barbiturates, several workers investigated the relationship between partition coefficient and structural parameters (Taft s polar and steric substituents constants, number of C-atoms) of these compounds.548,549 Partitioning of barbiturates was also proved to be a significant factor for their... 

In addition to this nonlinear relationship for the blood-brain barrier permeation of imidazolines, many other nonlinear lipophilicity relationships have been derived for buccal and gastrointestinal absorption, skin permeation, as well as blood-brain and blood-placenta barrier permeation (e.g., Eqs. (58) to (62) Fig. 7 [59,60,63,64] Barbiturates permeation through an organic membrane ... 

Figure 7 The permeation of barbiturates through an organic membrane, the gastric and intestinal absorption of carbamates, the blood-placenta transfer rate constants of various drugs, and the neurotoxicity of homologous primary alcohols, as a measure of blood-brain barrier permeation, follow nonlinear lipophilicity relationships (Eqs. (58)-(62)). (From Refs. 58,59,62,63.)...

It has been observed that the sodium barbiturates , in general, exhibit extremely lipophilic property that may cause distinct and rapid chemical incompatibility reactions, such as precipitation, when such compoimds are inadvertently brought in contact with the acid salts of relatively weak basic amines. 

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