Drug lipophilicity

Mannhold, R., Dross, K. P., Rekker, R. F. Drug lipophilicity in QSAR practice ... 

Kaliszan, R., Haber, P., Baczek, T., Siluk, D. Gradient HPLG in the determination of drug lipophilicity and acidity. Pure Appl. Chem. 2001, 73, 1465-1475. 

Rekker, R. F., Mannhold, R. Calculation of Drug Lipophilicity. The Hydrophobic Fragmental Constant Approach, VCH, Weinheim, 1992. 

FIGURE 4. Correlation between the relative inhibitory potencies of various drugs at high- and low-affinity [ H]MDA binding and between drug lipophilicities and inhibition potencies of [ H]MDA binding... 

Figure 7 Influence of drug lipophilicity (log PC) on the ratio of corneal to conjunctival permeability coefficients of beta-blockers. (From Ref. 158.)...

Camenisch, G., Alsenz, J., van de Waterbeemd, H., Folkers, G., Estimation of permeability by passive diffusion through Caco-2 cell mono-layers using the drugs lipophilicity and molecular weight, Eur. J. Pharm. Sci. 1998, 6, 313-319. 

D. J., Roffey, S. J., Jezequel, S. G., Abbott, N. J., The effect of drug lipophilicity on P-glycoprotein-mediated colchicine efflux at the blood-brain barrier, Int. J. Clin. Pharmacol. Ther. 1998, 36, 84-86. 

The affinity of the various stabilized dipeptidyl prodrugs to hPepTl in Caco-2 cells was also investigated [42, 43, 50]. In the case of the D-Glu-Ala ester-linked benzyl alcohols, an improved hPepTl affinity with increasing drug lipophilicity was observed [50], Furthermore, these model prodrugs are transported trans-epithelially across Caco-2 cells by virtue of a hPepTl-mediated process [50]. Preliminary hPepTl affinity studies made on Asp-Sar- and Glu-Sar-based (model)-... 

Dressman et al. [13] developed a dimensionless absorption potential (AP) model based on the concept that the fraction of dose absorbed, assuming negligible luminal instability and first-pass metabolism, is a function of drug lipophilicity (log P0/w), solubility (Sw), and dose (D), as defined in Eq. 2.7. 

The coexistence of lipid and water solubility in the same molecule is essential for the action of a local anaesthetic drug. Lipophilicity permits the migration of drug across the phospholipid membrane of the nerve cell hydrophilicity is essential for the ionisation of the drug within the nerve. It follows that lipid and water solubility are the external and internal facilitators of local anaesthetic action in the nerve cell. Both within and without the nerve cell the unionised and ionised forms coexist in dynamic equilibrium. Outside the nerve, the active species is the unionised tertiary amine form. Conversely, inside the cell the ionised form predominates. The lower intracellular pH induces a shift in the equilibrium in favour of ionisation (Figure 5.5). 

R. F. Rekker, R. Mannhold, Calculation of drug lipophilicity the hydrophobic fragmentat constant approach, VCH, Weinheim, Germany, 1992. 

Noguchi, T., W.N. Charman, and V.J. Stella. 1985. The effect of drug lipophilicity and lipid vehicles on the lymphatic absorption of various testosterone esters. Int J Pharm 24 173. 

Unionized form of the drug=lipophilic membrane transport ... 

The pKa is an important physicochemical parameter. The analyte pKa values are especially important in regard to pharmacokinetics (ADME—absorption, distribution, metabolism, excretion) of xenobiotics since the pKa affects the apparent drug lipophilicity [59]. Potentiometric titrations and spectrophome-tric analysis can be used for pKa determination however, if the compound is not pure, is poorly soluble in water, and/or does not have a significant UV chromophore and is in limited quantity, its determination may prove to be challenging. 

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