Clearance physiological approach

Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clin Pharmacol Ther 1975 18 377-390. 

Figure 4.4 Physiological approach to understanding clearance. CO, cardiac output VRH, venous return to the heart. Q, blood flow rate through the organ E, extraction ratio Db, mass of drug in the body at a given time.

Ito K and Houston JB. Prediction of human drug clearance from in vitro and preclinical data using physiologically based and empirical approaches. Pharm Res 2005 22 103-12. 

Temperature influences skin permeability in both physical and physiological ways. For instance, activation energies for diffusion of small nonelectrolytes across the stratum corneum have been shown to lie between 8 and 15 kcal/mole [4,32]. Thus thermal activation alone can double the rate skin permeability when there is a 10°C change in the surface temperature of the skin [33], Additionally, blood perfusion through the skin in terms of amount and closeness of approach to the skin s surface is regulated by its temperature and also by an individual s need to maintain the body s 37° C isothermal state. Since clearance of percuta-neously absorbed drug to the systemic circulation is sensitive to blood flow, a fluctuation in blood flow might be expected to alter the uptake of chemicals. No clear-cut evidence exists that this is so, however, which seems to teach us that even the reduced blood flow of chilled skin is adequate to efficiently clear compounds from the underside of the epidermis. 

The drawback of this approach is that it is essentially empirical, and does not allow for differences in metabolic clearance between the species, i.e., it assumes that clearance is proportional to blood flow. This works well for compounds that are highly extracted in the liver, and/or where passive renal clearance is the major pathway [5, 68]. An approach for compounds that are actively secreted into the urine has also been proposed [69], although the precise values of some of the physiological scaling factors have been questioned [70]. 

Another method of predicting human pharmacokinetics is physiologically based pharmacokinetics (PB-PK). The normal pharmacokinetic approach is to try to fit the plasma concentration-time curve to a mathematical function with one, two or three compartments, which are really mathematical constructs necessary for curve fitting, and do not necessarily have any physiological correlates. In PB-PK, the model consists of a series of compartments that are taken to actually represent different tissues [75-77] (Fig. 6.3). In order to build the model it is necessary to know the size and perfusion rate of each tissue, the partition coefficient of the compound between each tissue and blood, and the rate of clearance of the compound in each tissue. Although different sources of errors in the models have been... 

There are several approaches to pharmacokinetic modelling. These include empirical, compartmental, clearance-based and physiological models. In the latter full physiological models of blood flow to and from all major organs and tissues in the body are considered. Such models can be used to study concentration-time profiles in the individual organs and e. g. in the plasma [57-60]. Further progress in this area may result in better PK predictions in humans [61]... 

Labeling of iodinated aromatics with radioactive or has proved to be a valuable approach to measure GFR in nuclear medicine. Prominent among these is sodium iothalamate, which is specifically marketed in the US for GFR measurement by the name Glofil . Studies have shown that the clearance of this marker by the glomeruli is reproducible, simple, reliable and accurate, especially in children and those with advanced renal diseases [234]. This marker can also be administered by subcutaneous infusion to obtain GFR values without the need for urine collection [235]. Since very low doses (nanomolar scale) of radioactive aromatics are administered, monitoring of renal function may be achieved without disruption of normal physiologic functions. Concerns over radioactivity and associated handling costs may prevent the use of these compounds for routine GFR measurements. 

Clearance may also be viewed as the loss of drug from an organ of elimination such as the liver or kidney. This approach enables evaluation of the effects of a variety of physiological factors such as changes in blood flow, plasma protein binding, and enzyme activity. Therefore, total systemic clearance is determined by adding the clearance (CL) values for each elimination organ or tissue ... 

The PPK approach estimates the joint distribution of population specific pharmacokinetic model parameters for a given drug. Fixed effect parameters quantify the relationship e.g. of clearance to individual physiology like function of liver, kidney, or heart. The volume of distribution is typically related to body size. Random effect parameters quantify the inter-subject variability which remains after the fixed effects have been taken into account. Then the observed concentrations will still be randomly distributed around the concentration time course predicted by the model for an individual subject. This last error term called residual variability... 

As discussed in Chapter 30 and elsewhere (13), interspecies scaling is based upon allometry (an empirical approach) or physiology. Protein pharmacokinetic parameters such as volume of distribution (Pd), elimination half-life (b/2)/ and elimination clearance (CL) have been scaled across species using the standard allometric equation (14) ... 

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