Relationships between lipophilicity

Hansch C. Qnantitative relationships between lipophilic character and drng metabolism. Drug Metab Rev 1972 1 1-14. 

A comparahve analysis of coefficients and descriptors clarifies the relationship between lipophilicity and hydrophobicity (Y in Eq. 4 is the molar volume which assesses the solute s capacity to elicit nonpolar interactions (i.e. hydrophobic forces) which, as also clearly stated in the International Union of Pure and Applied Chemistry definitions [3] are not synonyms but, when only neutral species are concerned, may be considered as interchangeable. In the majority of partitioning systems, the lipophilicity is chiefly due to the hydrophobicity, as is clearly indicated by the finding that the product of numerical values of the descriptors V and of the coefficient v is larger in absolute value than the corresponding product of other couples of descriptors/coefficients [9]. This explains the very common linear rela-... 

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based ... 

Relationships between lipophilicity and retention parameters obtained by RPLC methods using isocratic or gradient condition are reviewed. Advantages and limitations of the two approaches are also pointed out, and general guidelines to determine partition coefficients in 1-octanol-water are proposed. Finally, more recent literature data on Hpophilicity determination by capillary electrophoresis of neutral compounds and neutral forms of ionizable compounds are compiled. Quotation is restricted to key references for every method presented - an exhaustive listing is only given for the last few years. 

Chou, C. H., Rowland, M. Relationship between lipophilicity and protein binding of a homologous series of barbimrates. Chin. Pharm. f 2002, 54, 87-94. 

C. Hansch and W.J. Dunn III, Linear relationships between lipophilic character and biological activity of drugs. J. Pharmaceut. Sci., 61 (1972) 1-19. 

Briggs, G.G., Bromilow, R.H. and Evans, A.A., Relationships between lipophilicity and root uptake and translocation of non-ionized chemicals by barley, Pestic. Sci., 13, 495-504, 1982. 

Hansch C and Dunn WJ (1972) Linear Relationships Between Lipophilic Character and Biological-Activity of Drugs. J Pharm Sci 61 pp 1-19. 

Fig. 4.4 Relationship between lipophilicity and CNS penetration expressed as free drug AUC ratio in brain to blood (data from reference [16]).

Fig. 5.6 Relationship between lipophilicity and renal clearance for SM-10888 and its metabolites.

Fig. 5.7 Relationship between lipophilicity and unbound renal (squares) and metabolic clearance (triangles) for a range of neutral drugs in...

Fig. 6.1 Relationship between lipophilicity and unbound renal clearance (highlighting GFR and urine output) for a series of neutral drugs in man.

Fig. 6.2 Relationship between lipophilicity, GFR and unbound renal clearance for neutral, acidic and basic drugs in man.

Fig. 6.4 Relationship between lipophilicity and total and unbound renal clearance in the dog for a series of class III antidysrhythmic agents (compounds 1 to 4 in Figure 6.3).

As the pharmacokinetic properties of the azomethine prodrugs of (7 )-a-methyl-histamine (12) were found to strikingly depend on their physico-chemical properties, it was attempted to quantify the relationship between lipophilicity and CNS penetration of the benzophenone derived imines [50], The main obstacle to the experimental measurement of the azomethines log P values was the competing hydrolysis of the... 

Fig. 13. Relationships between lipophilic antioxidants and lipid hydroperoxides in irradiated skin. (A) There was no relationship between decrease in a-tocopherol and appearance of lipid hydroperoxides. (B) There was a significant (p < 0.05) relationship between decrease in total Q (quinols + quinones) and appearance of lipid hydroperoxides.

Type I binding of drugs has been associated with their metabolism/435 This prompted a study(94) of N- demethylation of 4,5-epoxymorphinans with 3-O-alkyl functions from C, to C12. There was no simple relationship between lipophilicity and the rate of metabolism and maximal Type I binding was the same for all analogs. 

The relationship between lipophilic membrane permeability and Kow is well described in the literature. Kitagawa, Li, and Sato reported that permeability coefficients across excised skin increased directly with Kow for a homologous series of parabens. As is from the data in Table 3.1, greater permeability is directly related to greater lipophilicity (higher 7T w) J5... 

Relationship between lipophilicity and drug metabolism by linking to an... 

HANSCH, C. (1972) Quantitative relationships between lipophilic character and drug metabolism. 

Terasaki, T. Nouda, H. Tsuji, A. Relationship between lipophilicity and binding affinity with human serum albumin for penicillin and cephem antibiotics. J.Pharmacobiodyn., 1992, IS, 99—106... 

Roussel and Popescu [54] extended this work by developing a lipophilicity parameter, log k w The authors were able to explain the relationship between chiral retention of the enantiomers and their lipophilic interactions with the CSPs. Quantification of the influence of structural parameters Xi, X2 and X3 was also possible. The relationship between lipophilicity and chiral chromatographic behavior was explained for compounds 23-30 and an extension to other alkyl substituted atropisomers was made. A related study concerning the resolution of 23-30 on various p-methylbenzoyl cellulose beads has also been published [55] but will not be described here because it employs the same methodology as above. 

Figure 5.7 Root concentration factor (log RCF) expressed as a function of log Ko. O, 0-methylcarbamoyloximes x, substituted pbenylureas. [Reproduced from G. G. Briggs, R. H. Bromilow, and A. A. Evans, Relationships between lipophilicity and root uptake and translocation of non-ionised chemicals by barley Pestic. Sci, 13, 495. Copyright 1982, Society of Chemical Industry. Reproduced with permission granted by John Wiley and Sons, Ltd on behalf of the S.C.I.]...

---