Pharmacokinetic Studies in Developmental Toxicology: Practical Considerations and Approaches

Abstract

This article provides an overview of key practical considerations, approaches, and techniques to obtain pharmaco-/toxicokinetic information in pregnant and lactating animals. First discussed are selection of the route and time of exposure, the timing and frequency of blood/tissue sampling, the number of animals required, and statistical considerations. Dosing and sampling methods are described with particular reference to good technique for minimal impact on the pharmacokinetic processes being measured. Next, some applied techniques for aiding pharmacokinetic investigation are discussed. These include mass-balance metabolism, determination of protein binding, radiolabel distribution studies such as whole-body autoradiography, applications of constant-rate infusion dosing, and the uses of rodent whole-embryo culture. The potential for physiologically based pharmacokinetic modeling in developmental toxicology is introduced, and approaches for determining tissue/blood partition coefficients and metabolic rate constants for toxic chemicals are discussed briefly. Last, there is a short section on sample preparation and analysis, focusing on delicate samples such as embryonic material, and the power of analytical tools such as mass spectrometry and nuclear magnetic resonance spectroscopy. Examples of these techniques and approaches, as they apply to developmental toxicological research, are given wherever possible.

Key Words: :

• Pharmacokinetics
• Developmental toxicology
• Pregnant/lactating animals