Journal of Pharmaceutical and Biomedical Analysis 100 (2014) 94–102 Contents lists available at ScienceDirect Journal of Pharmaceutical and Biomedical Analysis j o ur nal ho me page: www.elsevier.com/lo cate/jpba Modeling the drugs’ passive transfer in the body based on their chromatographic behavior Maria G. Kouskoura a , Kyriakos G. Kachrimanis b , Catherine K. Markopoulou a,∗ a Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124, Greece b Department of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124, Greece a r t i c l e i n f o Article history: Received 18 February 2014 Received in revised form 24 July 2014 Accepted 25 July 2014 Available online 4 August 2014 Keywords: Drug-likeness Butyl column RP-HPLC PLS ANNs a b s t r a c t One of the most challenging aims in modern analytical chemistry and pharmaceutical analysis is to cre- ate models for drugs’ behavior based on simulation experiments. Since drugs’ effects are closely related to their molecular properties, numerous characteristics of drugs are used in order to acquire a model of passive absorption and transfer in the human body. Importantly, such direction in innovative bio- analytical methodologies is also of stressful need in the area of personalized medicine to implement nanotechnological and genomics advancements. Simulation experiments were carried out by examining and interpreting the chromatographic behavior of 113 analytes/drugs (400 observations) in RP-HPLC. The dataset employed for this purpose included 73 descriptors which are referring to the physicochemical properties of the mobile phase mixture in different proportions, the physicochemical properties of the analytes and the structural characteristics of their molecules. A series of different software packages was used to calculate all the descriptors apart from those referring to the structure of analytes. The correlation of the descriptors with the retention time of the analytes eluted from a C 4 column with an aqueous mobile phase was employed as dataset to introduce the behavior models in the human body. Their evaluation with a Partial Least Squares (PLS) software proved that the chromatographic behavior of a drug on a lipophilic stationary and a polar mobile phase is directly related to its drug-ability. At the same time, the behavior of an unknown drug in the human body can be predicted with reliability via the Artificial Neural Networks (ANNs) software. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Pharmacokinetics refers to the actions taken by the human body to deal with a medicine. These actions involve drug absorption into the body, distribution of the drug to various tissues, metabolism and excretion (ADME); with absorption being the most significant of the aforesaid processes. At the same time, drug-likeness can be defined as a com- plex balance of a variety of molecular properties and structural Abbreviations: ADME, Absorption Distribution Metabolism Excretion; ANNs, Artificial Neural Networks; log D, octanol/water distribution coefficient; log P, octanol/water partition coefficient; PAPMA, Parallel Artificial Membrane Perme- ability Assay; PCA, Principal Component Analysis; PLS, Partial Least Squares; PRESS, prediction error sum of squares; RMSEE, Root Mean Square Error of Estimation; RMSEP, Root Mean Square Error of Prediction; RP-HPLC, reversed phase high per- formance liquid chromatography; R 2 , correlation coefficient; Q 2 , prediction ability. ∗ Corresponding author. Tel.: +30 2310 997665; fax: +30 2310 997652. E-mail address: amarkopo@pharm.auth.gr (C.K. Markopoulou). features which determine whether a particular molecule is simi- lar to known drugs. A traditional method to evaluate a likely orally active drug for human is to check compliance of Lipinski’s Rule of five [1]. The rule is based on the observation that most drugs are relatively small and lipophilic molecules and describes molec- ular properties which are important for drugs’ pharmacokinetics. Over the past decade Lipinski’s research has led to further investi- gation by scientists to extend profiling tools to lead-like properties of compounds hoping that a better starting point in early discov- ery can decrease both experimental time and cost. Some methods allow, by using the Rule of Five and/or other properties, to rapidly identify compounds that could be more suitable for high through- put screening and for parallel synthesis efforts. According to Ghose et al. [2], a drug-like molecule has a logarithm of octanol/water par- tition coefficient (log P) between -0.4 and 5.6, molecular weight (M.W.) 160–500 g/mol, molar refractivity (MR) of 40–130, num- ber of atoms 20–70 and polar surface area not greater than 140 ˚ A 2 . Five properties have also been found to be of importance in oral administration by Lobell et al. [3]. Such boundaries are still http://dx.doi.org/10.1016/j.jpba.2014.07.031 0731-7085/© 2014 Elsevier B.V. All rights reserved.