Barbiturate octanol-water partition coefficient

The studies with barbiturates revealed that the logarithm of the retention time is linearly related to the octanol/water partition coefficients [66,67]. It has been observed that the retention index of the drug is linearly related to the octanol/water partition coefficient (logP), and that results are very close to that of the 2-keto alkane standard (solid line in Fig. 15.9). 

Materials that are solubilized in polyethylene glycol can be solubilized in the polyoxyethylene chains on the surface of a nonionic micelle. Ismail, Gouda, and Motawi found that the micellar partition coefficients of barbiturates in polysorbates 20, 40, 60, and 80 is a function of the solute substituents and is proportional to the octanol-water partition coefficient of the barbiturate. Similarly, Ikeda, Kato, and Tukamoto showed that the solubilization of alkyl barbiturates by polyoxyethylene lauryl ether is not dependent upon the number of carbons in the substituents. Since the different polysorbates contain different aliphatic groups, the rather small dependence of solubilization upon polysorbate number (i.e., upon alkyl chain length) suggests that the barbiturates are not solubilized primarily in the hydrocarbon portion of the micelle. Gouda, Ismail, and Motawi showed that the solubilization of barbiturates in polyoxyethylene stearates is proportional to the number of polyoxyethylene units in the surfactant. 

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. 

In a subsequent study, Hansch reported that the induction of cytochrome P450 by a series of 5,5-substituted barbiturates was directly related to their hydrophobicity (105). Analysis of the in vitro data for barbiturate-induced P450 in cultured chick hepatocytes yielded Equation 5.7, where C is the drug concentration that caused a 50% increase in cytrochrome P450 and P is the octanol-water partition coefficient. 

Hansch and coworkers, in their continuing attempts to place the discussion of structure-activity relationships of biologically active compounds on a mathematic basis, have presented evidence that the hypnotic activity of groups of barbiturates depends almost entirely on their relative lipophilic character as defined by their octanol-water partition coefficients. Although hypnotic activity was the model, the principle should apply to other actions of drugs in the central nervous system. 

Several authors have noted a relationship between the lipophilicity of the solubilizate, expressed as its partition coefficient between octanol and water, Pocianob its Saturation distribution between micelles and the aqueous phase. Rank-order correlations between the amount of substituted barbituric acid solubilized by polyoxyethylene stearates and their Poctanoi values have been reported by Ismail et al. [133]. Similarly the partition coefficients of several steroids between water and micelles of long-chain polyoxyethylene non-ionic surfactants have been correlated with their ether/water partition coefficients [145], Fig. 5.18 shows a linear relationship between the partition coefficient of a... 

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. 

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... 

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