Regional pharmacokinetics II. Experimental methods

Abstract

Regional pharmacokinetics is the study of the drug concentrations in specific regions of the body. It allows greater insight into the mechanisms of drug disposition than the study of systemic blood concentrations. Experimental methods in regional pharmacokinetics and their applications and limitations are reviewed. Post-mortem tissue biopsies give the drug concentrations in highly specific regions of the body, but require a large number of animals. Serial tissue biopsies yield the time-course of drug concentrations in individual animals, but have limited applications. Regional blood sampling in vivo requires catheterization of blood vessels and a measure of regional blood flow, but allows repeated measurements of the time-course of regional drug concentrations in an individual. In contrast, artificially perfused regions allow greater control of perfusate flow and composition, but are less representative of the in vivo situation. These factors can be retained in some animals by surgically transplanting organs to another location to increase access. Tissues slices and cell cultures can examine drug uptake in the absence of perfusion, and tissue homogenates can be used to study the in vitro rates of drug metabolism and tissue drug binding.

Human subcutaneous tissue distribution of fluconazole: comparison of microdialysis and suction blister techniques

“…However, obtaining samples of human tissues is problematic due to the invasive nature of tissue sampling procedures. Tissue biopsy is the most common method used in the study of drug tissue distribution in humans but this approach has limitations with respect to the number of samples that can be collected per subject and therefore the sparse nature of the data obtained [4, 5]. Furthermore, because homogenization disrupts all tissue components, the drug concentration obtained using this technique represents an average tissue concentration across the whole tissue, including residual blood entrapped in the tissue, intracellular fluid, interstitial fluid and structural tissue components.…”

I.V. Bolus Administration of Subconvulsive Doses of Lignocaine to Conscious Sheep: Myocardial Pharmacokinetics

“…Toxicity is characterized by both CNS effects and myocardial depression, and its narrow margin of safety has led to the investigation of its whole body and myocardial pharmacokinetics in both experimental animals and human patients [4][5][6]. Nevertheless, the limited number of methods available [7] and the difficulty of studying acute drug distribution in the myocardium have caused our understanding of the myocardial regional pharmacokinetics of drugs such as lignocaine to be far from complete [3]. In the previous paper in this series [8], we showed that lignocaine caused dose-dependent depression of myocardial contractility at doses small enough not to produce overt CNS effects.…”