The Concept of Clearance

Most of the clinical laboratory information used to assess kidney function is derived from or related to measurement of the clearance of some substance by the kidneys. The renal clearance of a substance is defined as the volume of plasma from which the substance is completely cleared by the kidneys per unit of time. Provided a substance S is in stable concentration in the plasma is physiologically inert freely filtered at the glomerulus and neither secreted, reabsorbed, synthesized, nor metabolized by the kidney, then the amount of that substance filtered at the glomerulus is equal to the amount excreted in the urine (i.e., the amount of S entering the kidney must exactly equal the amount leaving it). The amount of S filtered at the glomerulus = GFR multiplied by plasma S concentration GFR X PS. The amount of S excreted equals the urine S concentration (US) multiplied by the urinary flow rate (V, volume excreted per unit time). 

V = volumetric flow rate of urine in milliliters per minute 

Ps = plasma concentration of the substance The term (U5 x V)/Ps is defined as the clearance of substance S and is an accurate estimate of GFR providing the aforementioned criteria are satisfied. Inulin satisfies these criteria and has long been regarded as the most accurate (gold standard) estimate of GFR (see below). 

Kidney size and GFR are roughly proportional to body size. It is conventional therefore to adjust clearance estimates to a standard body surface area (BSA) of 1.73 m, according to the formula devised by Du Bois and Du Bois in 1916 h 

A variety of exogenous (radioisotopic and nonradioisotopic) and endogenous markers have been used to estimate clearance (Table 24-2). Measurement of clearance may require accurate measurements of both plasma and urinary concentrations of the marker used plus a reliable urine collection. For a reliable plasma measurement, the substance must have reached a steady-state concentration and not be rapidly changing. For a reliable urine collection, the urine flow must be adequate (several mL/min), the collection period of long enough duration, and complete bladder emptying achieved these requirements are problematic. 

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The concept of clearance is useful in pharmacokinetics because clearance is usually constant over a wide range of concentrations, provided that ehmination processes are not saturated. Saturation of biotransformation and excretory processes may occur in overdose and toxic okinetic effects should be considered. If a constant fraction of drug is eliminated per unit time, the elimination follows first-order kinetics. However, if a constant amount of drug is eliminated per unit time, the elimination is described by zero-order kinetics. Some drugs, for example, ethanol, exhibit zero-order kinetics at normal or non-intoxicating concentrations. However, for any drug that exhibits first-order kinetics at therapeutic or nontoxic concentrations, once the mechanisms for elimination become saturated, the kinetics become zero order and clearance becomes variable.3... 

Although the discussion thus far has defined the concept of clearance and presented several equations involving clearance, clearance as a mechanism of removing a drug from the body is likely still unclear. The link between bloodflow and drug... 

The elimination of drugs from the body can be described quantitatively using the concept of clearance, and this can be related to physiological events. 

The concept of clearance has found particular application in clinical work as it offers a simple relationship between dose rate (dose divided by the time interval between doses, D t and the average plasma concentration (c) of the drug... 

Because pharmacokinetics comprises the first few chapters of this book and figures prominently in subsequent chapters, we will pause here to introduce the clinically most important concept in pharmacokinetics the concept of clearance. In 1929, Moller et al. (22) observed that, above a urine flow rate of 2 mL/min, the rate of urea excretion by the kidneys is proportional to the amount of urea in a constant volume of blood. They introduced the term clearance to describe this constant and defined urea clearance as the volume of blood that one minute s excretion serves to clear of urea. Since then, creatinine clearance has... 

The concept of clearance is extremely useful in clinical pharmacokinetics because the systemic clearance of a drug is usually constant over the range of plasma concentrations of clinical interest. This is because the elimination of most drugs obeys first-order (linear) kinetics whereby a constant fraction is eliminated per unit of time. For drugs that exhibit dose-dependent elimination,... 

These elementary aspects of clearance may be revised in any textbook (e.g. Curry, 1980 Benet et al., 1996). The purpose of the remainder of this section is to show how much more informative the concept of clearance may be and to provide an illustration of its use. 

These principles include the role of physico-chemical properties the free drug hypothesis and the concept of clearance and scaling. Pharmacokinetic-pharmacodynamic simply stated these principles are ... 

The concept of clearance was developed by renal physiologists in the early 1930s as an empiric measure of kidney function. The pharmacokinetic basis of the term was defined at about the same time, with the recognition that the concept could be more generally applied to other organs and elimination pathways. 

The concept of clearance from regulatory control inoplies a removal of restrictions so that the cleared materials can be treated without any consideration of their radiological properties. However, the removal of restrictions may not always be conoplete drere is also the possibility of clearing... 

For areas identified as being part of a practice, the clean-up would be subject to the same considerations as any other routine activity within the practice, that is, the clean-iq> operation would have to be optimized by weighing the costs of clean-iq) against the benefits. The optimized solution would be constrained by appropriate dose constraints. In principle, the concept of clearance is also relevant here although it seems likely that the environmental concentrations derived on the basis of trivial doses will be too low to be of practical application in this context. 

EUROPEAN COMMISSION, Practical Use of the Concepts of Clearance and Exemption (Part I), RP-122, EC, Belgium (2001). 

This simplifies greatly the concepts of first-pass hepatic metabolism and systemic clearance referred to previously. Most importantly Cli is directly evolved from the enzyme kinetic parameters, V ax and K ... 

Despite the lack of anatomical identity the concept of apparent volume of distribution does have value. It can be considered as the volume from which a drug must be cleared. Thus, for a drug with a large VD, the plasma concentration during the terminal phase will decline slower than one with a smaller VDand similar clearance. This can be seen by rearranging the equation above ... 

In several disease states, the mucociliary clearance is impaired, and in such subjects the clearance from the tracheobronchial tree almost certainly exceeds 24 hours [33,34], making the concept of alveolar deposition in terms of retention in excess of 24 hours invalid. The slowly cleared material in normal subjects has... 

One problem with allometric scaling is that it is difficult for those not familiar with the concept to grasp the meaning of clearance as L/h-kg° and how it may... 

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