Barbiturates lipid-water partition coefficients

Barbiturates that have substituents in the 5 position promoting mure rapid metabolism (e.g.. by increasing the lipid/ water partition coefficient) than the intermediate group in-dude Pentobarbital-Sodiunit USP, sodium S-ethyl-S-( I methylbutyDbarbiturate (Nembutal) Secobarbital, IJSP, S-illyl-S-(l-melhylbutyl)barbiluric acid (Seconal) and the sodium salt sodium secobarbital. 

Hundreds of barbiturates have been synthesized on a trial-and-error basis. Although many structural features required for hypnotic activity have been recorded, no clear correlation between structure and activity has emerged. In 1951, Sandberg (43) made his fundamental postulation that to possess good hypnotic activity, a barbituric acid must be a weak acid and must have a lipid/water partition coefficient between certain limits. Therefore, only the 5,5,-disubstituted barbituric acids, the 5,5,-disubstituted thiobarbituric acids, and the 1,5,5-trisubstituted barbituric acids possess acceptable hypnotic, anticonvulsant, or anesthetic activity. All other substitution patterns, such as 5-monosubstituted barbituric acids, 1,3-disubstituted barbituric acids, or 1,3,5,5-tetrasubstituted barbituric acids, are inactive or produce convulsions. 

In the stomach (rat), it was found that drugs were absorbed well only if non-ionized. Thus, when the pH of the stomach contents was raised, basic drugs were better absorbed, because more of their molecules became non-ionized but this pH change decreased the absorption of acidic drugs, because less of the non-ionized form remained (see Section lo.o for an outline of the chemistry of ionization). The value of lipophilic properties in assisting absorption was demonstrated with three barbiturates of similar p Ca but different lipid/water partition coefficients (see Table 3.2) absorption rose proportionally as the coefficient rose (Schanker, Shore, Brodie and Hogben, 1957 Brodie, Kurz and Schanker, i960). The pattern... 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Fig. 9.7. Comparison between colonic absorption of barbiturates in the rat and lipid-to-water partition coefficient of the un-ionized form of the barbiturates. (From SchankerLS. Absorption of drugs from the colon. J Pharmacol Exp Ther 1959 126 283-294 with permission.)...

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