Drug lipophilicity

Meyer and Overton were the first to show a quantitative relationship between physicochemical and biological data in aliphatic systems. Their work related the activity of anesthetics to an olive oil-water partition coefficient, thus showing the importance of oil solubility for drug action.

Lipophilicity is a well-established factor in drug potency. Promazine and chlorpromazine, which differ substantially in activity, have essentially identical ionization potentials, but chlorpromazine has a dodecane/water partition coefficient of 366, while promazine has a partition coefficient of 42. That means that dodecane can "solubilize" about 9 molecules of chlorpromazine for every molecule of promazine. Since chlorpromazine has more affinity for lipid membranes than promazine, chlorpromazine is a more potent drug than promazine, and effective at smaller doses. The most potent drugs exhibit an optimum combination of lipophilicity and electron donating ability.

The importance of drug lipophilicity is illustrated by the example of bufotenin, which has a high-affinity for the 5-HT receptor but usually does not produce central effects, because bufotenin is deflected by a shield of fatty acids at the blood-brain barrier. Change bufotenin to its more lipid soluble isomere, 5-acetyl-N,N-dimethyltryptamine, and this drug elicits DMT-like intoxication. Once it has entered the CNS, 5-acetyl-N,N-dimethytryptamine can cross the blood-brain barrier, where it is hydrolyzed to bufotenin.

Lop P is obtained by measuring octanol-water partition coefficients. Nichols measured the log P values for 11 different substituted amphetamines, shown below. The ideal value predicted by this series of psychotomimetic amines is log P = 2.89-3.72.

From Lipophilicity, log P

Many CNS-acting drugs have log P > 2, but the potency begins to decrease if the value of log P is too high, which will decrease the rate of absorption of the drug. In the series above, activity drops off for methoxy-substituted amphetamines with log P>3.0. For LSD, log P = 2.96 (not shown).

It is not desirable to increase the lipid solubility of drugs over a certain value since most of the drug will become stuck to membranes and unable to achieve maximum concentration at the site of action. Conversely, drugs with a low value of log P are washed out since they are not lipophilic enough to stick to biological membranes. From principles of additivity, the number of carbon atoms is directly related to log P, thus the log P value of a drug can be increased simply by adding carbon atoms.

The relationship between activity and partition coefficients (log P) is due to the movement of hydrocarbons to the site of action. This movement is considered to be a random walk process with depends on the lipophilic character of the molecules. There is an ideal log P and any deviation from this value results in a slow rate of movement to the site of action and consequently, in a decrease in biological activity. Mathematically this results in a parabolic relationship between log A and log P (Barfknecht figure above).

Shulgin and colleagues have obtained an empirical relationship that relates the log P value and HOMO energy to a molecule's hallucinogenic activity, in mescaline units. It has been reported that the hallucinogenic potency of phenalkylamines is affected by the hydrophobic nature of the 4-substituent. For molecules without a hydrophobic 4-substituent, the first ionization potential energy was the determining factor. The simultaneous consideration of both ionization potential energy and lipophilicity provides better insight into the problem of hallucinogen activity than the consideration of electron donation potential alone.


References

Barfknecht C. F. and D. E. Nichols. (1975). Correlation of psychotomimetic activity of phenethylamines and amphetamines with 1-octanol-water partition coefficients. J. Med. Chem. 18, 208-210. 10.1021/jm00236a023

Kumbar M., V. Cusimano and D. V. Sankar. (1976). Quantum chemical studies on drug action V: Involvement of structure-activity, quantum chemical, and hydrophobicity factors in thrombocyte uptake of 5-hydroxytryptamine. J. Pharm. Sci. 65, 1014-1019. 10.1002/jps.2600650715

Nichols D. E., A. T. Shulgin and D. C. Dyer. (1977). Directional lipophilic character in a series of psychotomimetic phenethylamine derivatives. Life Sci. 21, 569-575. 10.1016/0024-3205(77)90099-6