1461-5347/99/$ – see front matter ©1999 Elsevier Science. All rights reserved. PII: S1461-5347(99)00180-7 ▼ Traditionally,lipophilicity is understood as the affinity of a compound or a molecular fragment for a lipidic environment, and it is expressed as the logarithm of the partition coefficient (log P) of a solute between two essentially immiscible solvent phases. Partition coefficients are obtained as a ratio of concentrations at equilibrium: Today, log P is a general notation, but it is not specific enough. To discuss actual cases, it is necessary to add a superscript defining the elec- trical state of the solute, and a subscript to indi- cate the solvent system. Superscripts are generally omitted for neutral forms, whereas a subscript is often omitted for the octanol–water system. Major lipophilicity molecular descriptors are contained in Table 1. The increasing number of lipophilic descrip- tors proposed in the literature is because of the relevance of lipophilicity in drug research and pharmaceutical sciences. In fact, drug action can be divided into two phases, a pharmacokinetic (PK) phase (effects exerted by a biological system upon a drug) and pharmacodynamic (PD) phase (effects exerted by a drug upon a biological sys- tem) 1,2 , lipophilicity being a major structural fac- tor able to influence both 3 . At the molecular level both PK and PD events could involve the same intermolecular 1 and intramolecular interactions between a drug molecule and a biological site (such as a membrane or receptor). Molecular lipophilicity descriptors specific for inter- or intramolecular effects thus appear as powerful tools in drug design. One approach to describing the intermolecular forces that govern the partitioning of neutral solutes is the so-called solvatochromic equation 4 , which factorizes lipophilicity into parameters de- scribing various properties of the solutes 5 : where V W is the calculated Van der Waals volume; *,  and  are the solvatochromic parameters (dipolarity/polarizability *, hydrogen-bond donor acidity  and hydrogen-bond acceptor ba- sicity ) and v, p, a and b are the regression coeffi- cients reflecting the contribution of each parameter to log P. Four types of isotropic solvent systems (the quartet of octanol–water, alkane–water, chloro- form–water and dibuthylether–water) express, in partly overlapping and partly complementary ways, the recognition forces that account for membrane partitioning and biological selectivity 6,7 . To over- come some experimental problems caused by the low alkane solubility of many compounds, 1,2- dichloroethane-water has become the system of log P = V W + p * + a + b + c P = [C] organic [C] aqueous Combined molecular lipophilicity descriptors and their role in understanding intramolecular effects Giulia Caron, Frédéric Reymond, Pierre-Alain Carrupt, Hubert H. Girault and Bernard Testa Giulia Caron Pierre-Alain Carrupt and Bernard Testa Institut de Chimie Thérapeutique Section de Pharmacie Université de Lausanne CH-1015 Lausanne Switzerland Frédéric Reymond Hubert H. Girault Laboratoire d’Electrochimie Ecole Polytechnique Fédérale de Lausanne CH-1015 Lausanne Switzerland All correspondence should be addressed to: Giulia Caron Dipartimento di Scienza e Tecnologia del Farmaco Via Giuria 9 I-10125 Torino Italy fax: +39 011 670 7687 e-mail: caron@pharm.unito.it reviews research focus 327 PSTT Vol. 2, No. 8 August 1999 Traditional lipophilicity parameters (log P and log D) are well-known physico-chemical descriptors largely used in QSAR studies. Besides their numerical value, log P data contain a variety of information about inter- and intramolecular forces affecting partitioning and its related biological phenomena. The deconvolution of information from log P can be accessed only by adequate interpretative tools, such as new lipophilic-combined descriptors, of which features and some applications are presented in this review. (1) (2)