Current Drug Metabolism, 2004, 5, 375-388 375 1389-2002/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd. Biopharmaceutic Classification System: A Scientific Framework for Pharmacokinetic Optimization in Drug Research Manthena V.S. Varma, Sateesh Khandavilli, Yasvanth Ashokraj, Amit Jain, Anandbabu Dhanikula, Anurag Sood, Narisetty S. Thomas, Omathanu Pillai, Pradeep Sharma, Rajesh Gandhi, Shrutidevi Agrawal, Vinod Nair and Ramesh Panchagnula * Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Phase X, SAS Nagar, Punjab 160062, India Abstract: The tenets of biopharmaceutics, solubility and permeability, are of pivotal importance in new drug discovery and lead optimization due to the dependence of drug absorption and pharmacokinetics on these two properties. A classification system for drugs based on these two fundamental parameters, Biopharmaceutic Classification System (BCS), provides drug designer an opportunity to manipulate structure or physicochemical properties of lead candidates so as to achieve better “deliverability”. Considering the facts for failure of NCEs, drug research, once concentrating on optimizing the efficacy and safety of the leads, dramatically transformed in the past two decades. With the enormous number of molecules being synthesized using combinatorial and parallel synthesis, high throughput methodologies for screening solubility and permeability has gained significant interest in pharmaceutical industry. Ultimate aim of the drug discovery scientist in pharmacokinetic optimization is to tailor the molecules so that they show the features of BCS class I without compromising on pharmacodynamics. Considerations to optimize drug delivery and pharmacokinetics right from the initial stages of drug design propelled need for “High Throughput Pharmaceutics” (HTP). In silico predictions and development of theoretical profiles for solubility and lipophilicity provides structure based biopharmaceutical optimization, while in vitro experimental models (microtitre plate assays and cell cultures) validate the predictions. Thus, biopharmaceutical characterization during drug design and early development helps in early withdrawal of molecules with insurmountable developmental problems associated with pharmacokinetic optimization. 1. INTRODUCTION In recent years, drug discovery program have dramati- cally changed from “empirical-based” to “knowledge-based” rational drug design. Advancements in biotechnology and combinatorial synthetic approaches, clubbed with high throughput screening (HTS) for pharmacological activity have converged the healthcare systems to produce increasing number of diverse new chemical entities (NCEs). However, this rational design of molecules does not necessarily mean rational drug delivery, since the drug molecules do not always deliver themselves [1]. Drug development in the past used to be initiated after identification of most active molecule. However this approach lead to a number of drawbacks with the problems being that many molecules which are put into development had poor physicochemical (solubility, stability) and biophar- maceutical (permeability and enzymatic stability) properties, as a consequence of which about 40% of NCEs fail to reach the market place [2]. Many investigational new drugs (INDs) fail during preclinical and clinical development, with an estimated 46% of compounds entering clinical development are dropped due to unacceptable efficacy and 40% due to safety reasons [3]. Pharmacokinetic optimization with *Address correspondence to this author at the Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Phase X, SAS Nagar, Punjab 160062, India; Tel: +91 0172 2214 682/687; E-mail: panchagnula@yahoo.com respect to ADME (absorption, distribution, metabolism and elimination) at the drug discovery phase would be most valuable in reducing NCEs failing in late preclinical and clinical development, since efficacy and safety issues are related in part to pharmacokinetic profiles. With the new pre- preclinical paradigm of compound optimization in early phase of drug discovery, pharmaceutical companies are working to integrate biopharmaceutical screening in the initial stages of drug discovery, in order to cut down the number of NCEs failing in the latter stages of drug development [4]. Fig. (1) shows the drug discovery phases and the integration of biopharmaceutical screening during lead optimization in the process of selecting candidates for preclinical and clinical development. Screening of libraries for solubility and perme- ability and the integration of charge state and/or physiolo- gical variables with these processes as the drug moves down the gastro intestinal tract (GI) provides useful biophar- maceutical screens in early development. This article covers the aspects of optimizing solubility and permeability, the fundamental properties of BCS which determines intestinal permeability of drugs, in the process of pharmacokinetic optimization for orally active compounds in drug research. 2. BCS AND ORAL ABSORPTION Peroral route of drug administration is the most preferred with respect to patient compliance and obvious commercial reasons. However, many molecules especially those resulting