Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5849_Библиотеки_им_академика_М_И_Перельмана

Attrition of drug candidates during the discovery and development process is a serious problem for the pharmaceutical industry. Other than a lack of in vivo efficacy or unintended toxicological issues, failures are often associated with inappropriate physicochemical characteristics contributing to poor absorption and poor pharma­cokinetics [1–3]. The absorption of any chemical entity reflects a very complex series of actions and efficacy can be affected by factors acting in concert or independently. In human physiology, for example, the physicochemical properties of the active ingredient, active or passive transport, disease state, formulation, and dose are often important for bioavailability. Other factors such as dosing interval, fed or fasted state, age, and gender can each affect the oral bioavailability of a given drug. Due to this complexity, optimizing absorption of a drug or formulation often requires full knowledge of how these variables interact. For a given compound it may take years of research before such comprehensive knowledge can be accu­mulated. In the absence of such detailed information on a new compound, optimization of a candidate to fit certain physicochemical properties and the corresponding first in human formulation is often based on common considerations of factors that affect absorption.