Classification Analysis of P-Glycoprotein Substrate Specificity

Abstract

Prediction of P-glycoprotein substrate specificity (S(PGP)) can be viewed as a constituent part of a compound's "pharmaceutical profiling" in drug design. This task is difficult to achieve due to several factors that raised many contradictory opinions: (i) the disparity between the S(PGP) values obtained in different assays, (ii) the confusion between Pgp substrates and inhibitors, (iii) the confusion between lipophilicity and amphiphilicity of Pgp substrates, and (iv) the dilemma of describing class-specific relationships when Pgp has no binding sites of high ligand specificity. In this work, we compiled S(PGP) data for 1000 compounds. All data were represented in a binary format, assigning S(PGP) = 1 for substrates and S(PGP) = 0 for non-substrates. Each value was ranked according to the reliability of experimental assay. Two data sets were considered. Set 1 included 220 compounds with S(PGP) from polarized transport across MDR1 transfected cell monolayers. Set 2 included the entire list of 1000 compounds, with S(PGP) values of generally lower reliability. Both sets were analysed using a stepwise classification structure-activity relationship (C-SAR) method, leading to derivation of simple rules for crude estimation of S(PGP) values. The obtained rules are based on the following factors: (i) compound's size expressed through molar weight or volume, (ii) H-accepting given by the Abraham's beta (that can be crudely approximated by the sum of O and N atoms), and (iii) ionization given by the acid and base pKa values. Very roughly, S(PGP) can be estimated by the "rule of fours". Compounds with (N + O) > or = 8, MW > 400 and acid pKa > 4 are likely to be Pgp substrates, whereas compounds with (N + O) < or = 4, MW < 400 and base pKa < 8 are likely to be non-substrates. The obtained results support the view that Pgp functioning can be compared to a complex "mini-pharmacokinetic" system with fuzzy specificity. This system can be described by a probabilistic version of Abraham's solvation equation, suggesting a certain similarity between Pgp transport and chromatographic retention. The chromatographic model does not work in the case of "marginal" compounds with properties close to the "global" physicochemical cut-offs. In the latter case various class-specific rules must be considered. These can be associated with the "amphiphilicity" and "biological similarity" of compounds. The definition of class-specific effects entails construction of the knowledge base that can be very useful in ADME profiling of new drugs.

Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

“…According to the "rule of fours," compounds with a molecular mass ,400 g/mol, sum of N and O atoms #4, and base pK a ,8 are probably not PGP substrates (Didziapetris et al, 2003). Thus, it was not self-evident to expect pilocarpine (molecular mass, 208 g/mol, sum of N and O atoms 5 4, pK a 5 6.78) to be transported by PGP.…”

Impact of P-Glycoprotein Inhibition and Lipopolysaccharide Administration on Blood-Brain Barrier Transport of Colistin in Mice

“…P-glycoprotein (P-gp) is one such efflux transporter and is responsible for restricting the brain penetration of a wide range of substrates, including anticancer drugs, analgesics, and antibiotics (27). Many of these substrates share some common physicochemical properties such as a positive charge at physiological pH and a molecular mass of Ͼ400 Da (7). Given that the primary amines of colistin possess a pK a value of approximately 10 and that colistin has a high molecular weight (19), it is plausible that the low brain uptake of colistin observed in our previous study (16) may also be due, in part, to P-gpmediated efflux.…”

Computational models for predicting drug transport mediated by P-glycoprotein

“…U kontekstu različite pouzdanosti klasifikacije jedinjenja u zavisnosti od tipa eksperimentalnih podataka, nekoliko autora predložilo je kriterijume koji omogućavaju uniformnu procenu nivoa dokaza koje dostupni podaci pružaju [19,40,46]. Usvajanje takvih kriterijuma prilikom prikupljanja eksperimentalnih podataka iz literature posebno je važno usled činjenice da postoji veliki broj primera jedinjenja koja su, primenom različitih testova, klasifikovana i kao supstrati i kao nesupstrati.…”