Preface

Book focuses on experimental in vivo and in vitro methods used to measure the ADMET properties (absorption, distribution, metabolism, excretion and toxicity) of potential drug candidates. Modern drug design also includes in silico computation methods to estimate ADMET properties, and several predictive methods are presented for drug solubility, blood-to-tissue partition coefficients, toxicity, nasal pungency and several other biological and sensory responses. One chapter is devoted to measurement uncertainty, bias and statistical treatment of experimental data. Analytical methods employed to identify and quantify genotoxic pharmaceutical impurities and drug metabolites are also described. Toxicity data from clinical studies are reported. Authors from several countries have contributed chapters detailing regulatory policies, pharmaceutical concerns and clinical practices in their respective countries. The open exchange of scientific results and ideas will hopefully lead to improved pharmaceutical products and a greater awareness of the vast toxicological issues that we all experience.

> **Dr. William Acree**  University of North Texas, United States

**Part 1** 

**Drug Design** 

**Part 1** 

**Drug Design** 

**1** 

*Iran* 

**Blood Brain Barrier Permeation** 

The large surface area and the short diffusion distance from capillaries of the blood brain barrier (BBB) to the neurons facilitate the drugs and nutrients access to the brain. Penetration of chemicals to the BBB occurs using a combination of intra and intercellular passages. Tight junctions regulate the intracellular passage of molecules according to their physico- chemical properties (e.g. lipophilicity, ionisation and polarity), where inter cellular penetration is regulated by influx and efflux transporters, endocytosis and passive diffusion. Poor pharmacokinetic properties (absorption, distribution, metabolism and excretion) and toxicity are responsible for most of the failures in drug discovery projects. This problem is more evident for CNS drugs because of the restrict barrier function of blood brain barrier. The CNS drug discovery attracted more attentions since the diseases pattern has been changed during recent decades and aging disorders are one of the major health problems. Drug exposure is controlled by plasma pharmacokinetic properties of drug which are different from brain pharmacokinetic and can be studied using common pharmacokinetic studies, where BBB permeability depends on physicochemical properties of drug compound and physiologic function of the BBB (physical barrier, transport, metabolic, …) and need special study techniques. In this chapter, fundamentals of BBB, permeation mechanisms, penetration measurement methods and penetration prediction methods are discussed.

BBB consisted of a monolayer of brain micro vascular endothelial cells (BMVEC) joined together by much tighter junctions than peripheral vessels and formed a cellular membrane which known as the main physical barrier of BBB (Abbott, 2005; Cardoso et.al., 2010). The main characteristics of this cellular membrane are, uniform thickness, no fenestrae, low pinocytotic activity, continues basement membrane and negative surface charge. In addition to the BMVECs, the neurovascular unit consisted of the capillary basement membrane, pericytes, astrocytes and microglia. The BMVECs are surrounded by a basement membrane which composed of structural proteins (collagen and elastin), specialized proteins (fibronectin and laminin) and proteoglycans. This structural specificity gives the basement membrane a cell establishment role. Pericytes are cellular constituents of microvessels

**1. Introduction** 

**2. Fundamentals of BBB** 

**2.1 Cellular properties of Blood Brain Barrier** 

Abolghasem Jouyban1 and Somaieh Soltani2 *1Drug Applied Research Center and Faculty of Pharmacy, 2Liver and Gastrointestinal Diseases Research Center,* 

*Tabriz University of Medical Sciences, Tabriz,* 
