Blood Flow Distribution and Membrane Transporters as Determinant Factors of Tissue Drug Concentration

The free drug hypothesis states that the non-ionized free drug concentrations will have the same value in all the aqueous spaces of the body, once the pseudo-equilibrium of distribution has been achieved and provided that there is no unidirectional transport at the capillary endothelium and the tissue cell’s membranes. Tissues require nutrients and oxygen to meet their basic needs. To provide each body tissue with the corresponding amount of these essential solutes carried by the blood, the cardiac output is distributed among them in proportion to their respective energy demands, independently of their sizes. The higher the need for fuels (glucose, fatty acids, etc.) and oxygen, the higher is the blood flow fraction delivered to the tissue. Thus, tissues can be viewed as highly or poorly perfused according to their blood flow/water content ratio. However, no physiological role exists for xenobiotics that enter the body (e.g., drugs, contaminants, food additives). To prevent unnecessary xenobiotics from overloading highly perfused tissues, efflux transporters are overexpressed in their membranes. The greater the fraction of blood flow that a tissue receives, the greater the extrusion of efflux transporter’s substrates from the tissue, either into the blood or out of the body. Occasionally, xenobiotics may highjack uptake transporters if they share some fundamental molecular features with the physiological substrates of these transporters. The distribution of the cardiac output and the action of transporters that carry the unbound drug against its concentration gradient determine its actual tissue unbound concentration, which can be very different between tissues and between extravascular space of tissues and blood. This new perspective has important consequences for the relationship between the intensity of therapeutic/toxic effect and plasma drug concentration, in the in vitro-in vivo extrapolation of drug clearance and in physiology-based pharmacokinetic (PBPK) modeling with a focus on drug tissue concentration. A PBPK analysis of drug exchange between blood and tissues according to this new paradigm leads to a more accurate forecast of drug disposition and action, mainly in the variant scenario provided by the circadian rhythm of the cardiovascular function.