Chapter 30 Prediction of Human Volume of Distribution Using in vivo, in vitro, and in silico Approaches
Introduction
It has become increasingly accepted that the pharmacokinetic behavior of new drugs represents an important attribute, along with efficacy and safety. The frequency with which a drug must be taken is a function of several factors: the half-life, the span between minimally efficacious concentrations and concentrations that cause side-effects, and the pharmacokinetic-pharmacodynamic relationship. Typically medicinal chemists optimize the predicted pharmacokinetics of compounds in humans and the potency and other compound attributes simultaneously. Predicted human half-lives can be lengthened by decreasing the predicted clearance, and it is now commonplace in drug research to screen the newly synthesized compounds for in vitro metabolic lability in assays using human-derived reagents (e.g., hepatic microsomes).
The half-life (t1/2) of a drug is a function of two variables: clearance and volume of distribution. Half-life is directly related to volume of distribution (VD) and inversely related to clearance (CL):Thus, while the half-life can be lengthened by reducing the clearance (as stated above), the half-life can also be lengthened by increasing the VD.
Section snippets
Volume of distribution: a fundamental definition
To understand VD at its most basic element, begin by considering a vessel with no volume markings on it that contains an unknown volume of solvent. Into this volume of solvent is dissolved a known mass of solute. Then, a sample of the solution is removed and the concentration of the solute is measured. By knowing the mass of solute added and subsequently measuring the concentration of the solution, the volume of the solvent can be computed:
General considerations
The accurate prediction of VD is clearly desired when making selections of new pharmacological agents for further development as drugs. Over the years, several types of approaches have been described that can be used for making such predictions. These approaches vary in the extent of effort needed to generate the data required for the prediction method. Obviously, methods requiring animal pharmacokinetic data are the most expensive and labor intensive, as they require synthesis of suitable
Conclusions
It can be concluded that many methods exist which can provide predictions of human VD values for new chemical entities with acceptable accuracy in drug research efforts. In the search for new drugs, those with acceptable pharmacokinetic properties are sought because reasonable and convenient dosing regimens will provide a better chance for therapeutic success. Since VD plays a role in what the half-life of the drug will be, this parameter is important to predict. The determinants of VD (i.e.,
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