Drug distribution perfusion rate

In perfusion models, as depicted in Fig. 3, it is assumed that distribution into and out of the organ is perfusion rate limited such that drug in the organ is in equilibrium with drug concentration in the emergent blood... 

Distribution is the delivery of drug from the systemic circulation to tissues. Once a drug has entered the blood compartment, the rate at which it penetrates tissues and other body fluids depends on several factors. These include (1) capillary permeability, (2) blood flow-tissue mass ratio (i.e., perfusion rate), (3) extent of plasma protein and specific organ binding, (4) regional differences in pH, (5) transport mechanisms available, and (6) the permeability characteristics of specific tissue membranes. 

The rate at which an equilibrium concentration of a drug is reached in the extracellular fluid of a particular tissue will depend on the tissue s perfusion rate the greater the blood flow the more rapid the distribution of the drug from the plasma into the interstitial fluid. Thus, a drug will appear in the interstitial fluid of liver, kidney, and brain more rapidly than it will in muscle and skin (Table 3.2). The pharmacokinetic concept of volume of distribution (a derived parameter that relates the amount of drug in the body to the plasma concentration) is discussed more fully in Chapter 5. 

The rate at which distribution takes place into a tissue is dependent on both the drug partition coefficient (concentration in tissue/concentration in blood at equilibrium) and the blood flow to that tissue. The higher the perfusion rate (blood flow per unit volume of tissue), the more rapid is equilibrium achieved between blood and tissue. The higher the partitioning into the tissue, the longer reaching equilibrium takes, as more drug has to be transported to the tissue. 

Note that the effect equilibration rate constant (ke0) may be viewed as a first-order distribution rate constant. It can also be thought of in terms of the rate of presentation of a drug to a specific tissue, determined by, for example, tissue perfusion rate, apparent volume of the tissue and eventual diffusion into the tissue. The results of the data fitting in this exercise with the analgesic are Emax 4.5 EC50 0.61 ng-ml 1 and e0 0.07 h1. 

Figure 7.9 A. Illustrates the differences in perfusion rate on the proposed distribution and redistribution of thiopental. (Redrawn from http //www.cvm.okstate.edu/Courses/vmed5412/LECT006.htm) B. Drug equilibration in the cerebrospinal fluid with plasma water for various drugs in the dog (redrawn from Figure 5-11 in Rowland and Tozer, 2006, and Brodie et al., 1960. Plasma drug concentration was kept constant throughout the study. Thiopental displays perfusion limited distribution whereas the distribution of salicylic acid is permeability rate limited.

In contrast to the BBB, the endothelium of the choroid plexus is fenestrated, hence the true barrier for drug distribution across the choroid plexus is formed by a single continous layer of epithelial cells whose principal function is to control cerebral spinal fluid (GSF) homeostasis (Figure 7.1 IB). It also has tight paracellular junctions, but the flux of drugs across this barrier is much less extensive than the BBB due to its lower perfusion rate and smaller surface area. 

Drug distribution can be defined as the (reversible) transfer of drug around the body. This is usually very quick within the vascular system but variable into tissues, being dependent on a number of factors including blood perfusion rate, drug diffusion rate, plasma protein binding, and tissue binding. 

The cardiac output or flow of blood normally is so rapid that the distribution of a drug or poison throughout the body is complete within a short period of time. An entire 6 liter supply of blood is pumped through the body at the rate of about once per minute. Some organs and tissues are more highly perfused with blood than others, such as the brain, heart, liver, and kidneys. Adipose (fat) tissue is not as richly endowed. Should a person be in shock or have suffered a myocardial infarction (heart attack), however, the cardiac output can be sharply diminished and a route of drug administration normally used may be circumvented because of poor... 

In this assay, immobilized platelets are pretreated with a GPIIb/IIIa antagonist, and any unbound drug is washed away before the perfusion of monocytic THP-1 cells. McCarty et al. (2004) demonstrated that agents with slow platelet off-rates such as XV454 (ti/2 of dissociation = 110 min Kd = 1 nM) and abciximab (ti/2 of dissociation = 40 min Kd = 9.0 nM) that are distributed predominantly as receptor-bound entities with little unbound in the plasma, can effectively block these heterotypic interactions as shown by Abulencia et al. (2001) and by Mousa et al. (2002). In contrast, agents with relatively fast platelet dissociation rates such as orbofiban (ti/2 of dissociation = 0.2 min Kd > 110 nM), whose antiplatelet efficacy depend on the plasma concentration of the active drug, do not exhibit any inhibitory effects as described by Mousa etal. (2002). 

Following GI absorption or IV administration, benzodk azepines are rapidly distributed to the CNS. Subsequently, benzodiazepines are more slowly redistributed from the CNS to more poorly perfused tissue, such as adipose tissue and muscle. The rate of this redistribution is an important determinant of the duration of action of benzodiazepines and, like that for GI absorption, is largely determined by drug lipophihcity, with the more lipophilic drugs, such as midazolam and triazolam, having the shortest duration of action. Additional factors that influence the duration of benzodiazepine action are hepatic metaboHsm and acute tolerance, resulting in decreased response to benzodiazepines with continued drug exposure. 

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