Solubility, Delivery and ADME Problems of Drugs and Drug-Candidates

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The basic objective of medicinal chemistry is to deliver not only potent in vitro chemicals, but also, more importantly, drug candidates that can be progressed to clinical trials and that will eventually reach the market. This is a long and winding road – one that is often tricky to follow and that sometimes reaches a dead end. Over the past few decades, the pharmaceutical industry has learned that ADME and related parameters are of pre-eminent importance in selecting a successful candidate. This chapter briefly discusses the most important physico-chemical and other more complex ADME parameters, while focusing on in silico prediction. Historical approaches are mentioned, but, as the title suggests, the emphasis is on recent advances. The authors’ intention is to help medicinal chemists to achieve their goal of identifying new therapeutic options for human diseases.

In the last two decades, the role of physicochemical parameters has come to the forefront of early stage drug discovery. The primary driver behind this revolution is the fact that the pharmacokinetic properties of hit and lead compounds have become worse and worse. In this chapter, the theoretical background and measurement techniques for the more important physicochemical parameters are introduced from the perspective of the ADME/T processes. Finally, during the last decade a number of significant ADME/T-physicochemical-based structure relationships have been shown to be relevant.

In the last several decades, drug research and development have faced a number of issues related to the pharmacokinetics of new chemical entities. Numerous new drug candidates have been reported to have failed in human clinical phases (mainly phase I) after oral administration due to ineffectiveness caused by unsatisfactory pharmacokinetics. The same problem is also occurring during preclinical research and development. It has been clearly demonstrated that solubility is one of the major factors affecting the in vivo systemic exposure of drug candidates. Drug companies usually aim to develop oral products, as this is the preferred administration route for medicines. The main administration route in the preclinical phase is also oral. Solubility is an issue not only in human clinical phases, but also in the preclinical stage. Keeping the factors affecting solubility in mind can help the researcher to achieve a satisfactory level of drug exposure. This chapter addresses the theoretics of solubility and the internal and external factors concerning the dissolution process, such as morphology, particle size, surface area, pH, ionic strength and surfactants. At the end of the chapter, there is a short overview of the practice of solubility measurement.

The success of the drug research and development process depends not only on the intrinsic qualities of the molecules, but also on the way in which these qualities can be revealed. The inherent efficacy of drug candidates can be manifested if a sufficient drug concentration can be ensured at the site of action. The purpose of preclinical formulation is to provide sufficient exposure for the in vivo evaluation and selection of new chemical entities (NCEs). Both conventional formulation approaches (pH adjustment, use of cosolvents and/or surfactants, cyclodextrin complexation) and novel formulations (microemulsions, solid dispersions, nanosuspensions) are described. In addition to describing the formulation technologies, the mechanisms behind their actions and the in vivo functions are discussed. The special formulation requirements of different stages of early drug research, including practical considerations, are also presented.

A high enough level of bioavailability (BA) is a prerequisite in order for a drug to take effect. Absolute bioavailability is the fraction of a dose that reaches systemic circulation following oral administration. The key determinants of the systemically available drug level are the amount of the dose that enters the enterocytes and the fraction that escapes as a result of metabolism by the gut wall and/or the liver. Body biology, drug properties and formulation factors all influence the outcome. In silico, in vitro and in vivo models for drug screening have been developed and are able to provide predictions for human absorption in accordance with the degree of complexity of the model.

This chapter provides a summary of the drug properties and biological variables in the gastrointestinal tract that influence drug absorption, and summarises the key models that have been developed and are in use for screening and predicting intestinal drug absorption.

The aim of this chapter is to describe the main in vitro assays used to predict the interaction of drugs with ABC efflux transporters, to highlight their characteristics and to discuss their advantages and disadvantages. In recent years, the number of synthesized compounds has increased dramatically as a result of advances in combinatorial chemistry; consequently, early prediction of the interactions of drug-like compounds with efflux transporters has garnered considerable attention. Moreover, transporter-related drug-drug interactions, particularly in specific groups (children and the elderly), are of great concern. The withdrawal of marketed drugs and the failure of drugs in the late clinical phase of drug research is often due to drug-drug interactions. Furthermore, regulatory authorities require information on the potential for interactions to cause adverse effects: a question that might be answered by in vitro assays even in the early stages of discovery. In vivo studies and cellbased assays such as CaCo-2 monolayers have been elaborated, as well as quite expensive screening modes that are primarily used for screening large numbers of compounds. By scaling the discussed in vitro assays up to medium- or high-throughput screening modes, these assays can be efficiently used for the prediction of active transport and transporter-mediated drug-drug interactions, and may be the most cost-effective approach to transporter screening in drug discovery.

The induction of enzymes is an adaptive tool in maintaining homeostasis. However, in drug development enzyme induction is an unwanted trait of NCEs. Enzyme inducers may alter the biotransformation of xenobiotics and endogenous compounds. The consequence of faster conversion is a therapeutic insufficiency or a too-high exposure to an active drug formed from its prodrug. An increased rate of reactive metabolite production originating from lower bioavailability and higher dosage may have toxicological significance. The sustained higher clearance of endogenous compounds, such as hormones, may have endocrinologic effects. Nuclear receptor activation by xenobiotics, which precedes downstream events, mediates highly pleiotropic effects, many of them unrelated to drug metabolism. The altered expression of various cell cycle regulating factors through nuclear receptors may have a considerable influence on the cell cycle, growth and differentiation. Apart from the potentially harmful effects of enzyme induction, increased metabolic enzyme activity is beneficial when exposure to harmful xenobiotics is reduced due to their higher clearance.

The inhibition of metabolic enzymes is a frequent underlying cause of drug-drug interactions. Assessment of the inhibitory potential of NCEs is a focus of ADME property screening in drug discovery. The prediction of in vivo drug-drug interactions based on in vitro-generated enzyme kinetic constants is a challenging task. As the inhibition of metabolic enzymes cannot be completely eliminated, low victim potential and low inhibitory propensities are of equal importance in selecting drug candidates.

The blood-brain barrier, a dynamic interface separating the brain from systemic circulation, is the major entry route for therapeutic compounds to the central nervous system. The blood-brain barrier phenotype of the endothelial cells of brain microvessels includes tight interendothelial junctions, the lack of pinocytosis and fenestrae, transendothelial transport pathways, and a metabolic barrier. The primary role of the blood-brain barrier is to create ionic homeostasis for neuronal functions, but it also provides the central nervous system with nutrients and protects it from toxic insults. The formation and maintenance of these organ-specific characteristics are based on cross talk between the cells of the neurovascular unit, such as brain endothelial cells, pericytes, astroglia, microglia and neurons. The problem of drug transport at the blood-brain barrier is two-fold: the great majority of neuropharmaceutical candidates, hydrophilic molecules, biopharmaceuticals and efflux transporter ligands do not penetrate the blood-brain barrier, while unwanted side effects develop if a drug with main peripheral action crosses the blood-brain barrier. Overcoming the major mechanisms restricting drug transport at the level of the blood-brain barrier, tight interendothelial junctions, efflux transporters and the enzymatic barrier can lead to better drug penetration to the brain. In addition, there are several physiological transport pathways – the carrier systems and the adsorptive and receptor-mediated transports – which can be exploited for drug targeting. Strategies for drug delivery and targeting to the brain include modification of the molecules, modification of the blood-brain barrier functions, and circumvention of the blood-brain barrier. Some of the techniques based on these strategies are already in clinical use, while others are promising new possibilities for improving the therapy of central nervous system diseases.

As the blood-brain barrier (BBB) prevents the majority of potential neurotherapeutics from reaching the central nervous system, early screening for BBB penetrability is very important in drug development. There are an abundance of available methods, from in silico screening through non-cell-based and cell-based in vitro methods to animal studies, with different predictive values, speed and throughput. Computational models and in vitro methods measuring physico-chemical properties, the octanol/water partition coefficient, and penetration through artificial membranes are accurate for predictions of passive permeability methods. Cell cultures including epithelial cell lines and their transporter transfected or drug-treated subclones and brain endothelial cell-based models in mono- and co-cultures with glial cells and/or pericytes are versatile tools for bi-directional active and passive transcellular transport. In vivo techniques to measure brain uptake, influx or efflux transport include brain perfusion, microdialysis, magnetic resonance imaging, positron emission tomography and, more recently, nearinfrared time-domain optical imaging. These research asnd screening tools for BBB permeability will be reviewed with a special emphasis on culture-based BBB models. While none of these methods can be used alone to generate a reliable prediction of drug transport through the BBB, a combination of different models can give a useful estimate of the brain penetrability of drug candidates in preclinical screening.

High molecular weight biomolecules are becoming increasingly important for the development of molecular therapies. However, these molecules cannot diffuse through the cell membrane the way traditional small molecule drugs can. The potential therapeutic use of such information-rich macromolecules has been limited by their poor permeability across the lipid bilayer of biological membranes. Different approaches have been used to develop biological agents, biophysical methods or mimicking natural processes to overcome the barrier function of the plasma membrane. The unique capability of special oligopeptides, known as cellpenetrating peptides (CPPs) or protein transduction domains (PTDs), opened the way to introducing biologically active macromolecules into living cells. These peptides, conjugated or complexed with the desired molecules, can be used in both in vitro and in vivo systems for the intracellular or intraorganellar delivery of large molecules. After the discovery of these small peptides, macromolecular transport across biological membranes has emerged as a valuable technique in basic research and a promising tool in in vivo preclinical models and clinical trials. This chapter attempts to give an overview of what kind of CPPs exist, how they function, what has been achieved and what can be achieved in the future with their use. It also aims to expose the limitations of the utilization of CPPs and the controversies regarding their potential, working mechanism and route of internalization. Finally, we want to discuss how virus-, liposome- and CPP-mediated techniques converge into new complex methodologies.

Drug delivery to the central nervous system (CNS) has long been recognised as an enormous task, due to the physiological gate-keeping function of the blood-brain barrier (BBB). With the development of molecular biology, the function and properties of the BBB are better understood. In this review, transporterization, a promising method for drug delivery by endogenous proteins, is discussed, and a survey of the reported results is presented.

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