What is the difference between elimination and clearance

For instance, Jambhekar and Breen offer the following:. Now, regarding "the fate of drugs in the body". G enerally speaking, there are only two possible fates. A drug can be excreted i. In either case, its is cleared and eliminated. The pursuit of definitions can trend towards the irrational. For instance, the concept of elimination and the concept of clearance. The terms are not synonymous in fact they are completely different things , even though they sound as if they might be interchangeable, and uneducated people might indeed use them interchangeably.

However it becomes clear from a brief period of reading that the textbook authors make a firm distinction between the term "clearance" and the term "elimination", even though this is not always explored to a satisfactory degree. Is there a hidden meaning in this? Can we conceive of a situation where we might find some use in having separate definitions for these terms?

Can one envision a world where one administers a drug which is eliminated but not cleared , for example? Before succumbing to eye-clawing madness , the author was able to determine that most textbooks refer to rate of elimination as the amount of substance cleared from the blood, whereas clearance seems to always be the volume of blood cleared of substance. Where this comes from, nobody can say certainly none of the textbook authors offer any sort of reference and so we are left to blame the early pioneers of renal medicine, from whose descriptions of creatinine clearance all of these pharmacokinetic concepts are adopted.

So, the elimination rate and the clearance rate of the same drug can be different. To be even more blunt, clearance is a completely independent primary pharmacokinetic parameter, which is not a measure of drug elimination. Consider: in first order kinetics, elimination rate is proportional to dose.

The higher the dose, the greater the rate of elimination. However, clearance rate remains dose-independent: it is a totally theoretical volume of blood which is cleared of the drug per every unit of time, a measure which has nothing to do with the drug dose or concentration.

As an example, consider diltiazem and felodipine. However, felodipine has a much larger volume of distribution times and therefore its elimination half-life is prolonged also by three to four times. The fundamental concept is that the total body clearance is the sum of all individual organ clearances. There are several different organ-specific clearance concepts, and a few other terms which need to be defined. Generally speaking, the renal clearance is the most important hence the college being so keen on using it in the exams.

The main reason for this is not that the kidneys are the major organ of drug clearance even though they are but because their tendency to produce urine offers the most convenient method of measuring drug clearance you just need to measure the urinary drug concentration. Other tissues such as kidney, lung, small intestine, and skin also contain biotransformation enzymes.

Drug elimination in the body involves many complex rate processes. Although organ systems have specific functions, the tissues within the organs are not structurally homogeneous, and elimination processes may vary in each organ.

In Chapter 3 , drug elimination was modeled by an overall first-order elimination rate process. In this chapter, drug elimination is described in terms of clearance from a hypothetical well-stirred compartment containing uniform drug distribution. The term clearance describes the process of drug elimination from the body or from a single organ without identifying the individual processes involved.

Clearance may be defined as the volume of fluid cleared of drug from the body per unit of time. The volume concept is simple and convenient, because all drugs are dissolved and distributed in the fluids of the body.

The advantage of the clearance approach is that clearance applies to all elimination rate processes, regardless of the mechanism for elimination. In addition, for first-order elimination processes, clearance is a constant, whereas the rate of drug elimination is not constant. For example, clearance considers that a certain portion or fraction percent of the distribution volume is cleared of drug over a given time period. This basic concept see also Chapter 3 will be elaborated after a review of the anatomy and physiology of the kidney.

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Learn More. Sign in via OpenAthens. Sign in via Shibboleth. AccessBiomedical Science. AccessEmergency Medicine. It is very important to distinguish between the dependent secondary parameters and independent primary parameters in equations 5. Clearance and volume of distribution are the primary pharmacokinetics parameters for elimination and distribution, respectively.

Primary parameters are independent parameters. Thus, clearance will not change if distribution changes, and volume of distribution will not change if elimination changes. In contrast, the elimination rate constant and the half-life are secondary or derived parameters.

As derived parameters, the elimination rate constant and half-life cannot change independent of clearance and volume of distribution, and cannot change either of these primary parameters. It is also important to appreciate that clearance is not a measure of the rate of drug elimination. It is one of the two factors Vd is the other that determine how quickly or slowly a drug is eliminated from the body. Many drugs that have high values of clearance are eliminated rapidly short half-lives.

For example, buspirone, didanosine, metoprolol, and morphine all have high clearances and short half-lives in the region of 1 to 2 h. Similarly, many drugs that have low clearances are eliminated slowly; for example, phenobarbital has a very low clearance and a half-life of around 4 days.

In both cases the majority of the drug in the body is located in the tissues and is inaccessible to the organs of elimination. In the kidney the parent drug may be eliminated by excretion into the urine. The value of renal clearance is determined by blood flow to the part of the kidney involved in drug excretion and on the ability of the kidney to excrete the drug.

The ability of the kidney to excrete the drug is a function of renal physiology and the physicochemical properties of the drug. The nephron is the functioning unit of the kidney, and each kidney possesses about 1 to 1. A simplified diagram of the nephron is shown in Figure 5. In the glomerulus, plasma water is filtered glomerular filtration into the renal tubule, the contents of which eventually drain into the bladder.

However, as the filtrate passes through the tubule, components such as water and dissolved substances, including drugs, may move back and forth across the renal tubule membrane between the blood and the lumen of the tubule.

The movement of compounds from the capillaries surrounding the tubules peritubular capillaries into the tubule is referred to as tubular secretion The movement in the opposite direction, from the tubules back into the blood, is referred to as tubular reabsorption During transit through the tubule, much of the plasma water is reabsorbed back into the bloodstream.

Three processes in the kidney participate in drug excretion: glomerular filtration in the glomerulus; tubular secretion, which takes place primarily in the proximal renal tubule; and tubular reabsorption, which occurs primarily in the distal renal tubule. In the glomerulus the blood is subjected to hydrostatic pressure, which forces plasma water and small solutes, including most drugs, through the capillary membrane and into the renal tubule.

The glomerular capillaries are extremely permeable and permit the free passage of neutral molecules below 4 nm in diameter. The filtration of compounds with diameters between 4 and 8 nm is inversely proportional to their size.

Compounds greater than 8 nm are excluded completely. The glomerular capillary wall appears to possess a negative charge, which repels negatively charged molecules. As a result, the permeability of anions is less than that of neutral molecules. Plasma proteins, including albumin, which has a negative charge and a diameter of about 7 nm, do not undergo any appreciable filtration 2. If a drug does not bind to plasma proteins and it is small enough to be filtered in the glomerulus, its clearance by glomerular filtration is equal to the glomerular filtration rate at this point, the filtrate, and any drug it contains, is eliminated and removed from the circulation.

It represents the volume of plasma completely cleared of drug:. However, many drugs bind to the plasma proteins, and bound drug will not be filtered. Drug elimination can be augmented further by tubular secretion, a process that results in the movement of drug from the blood in the peritubular capillaries that surround the tubule into the lumen of the tubule.

In many cases, this process is accomplished by the action of transporters, which appear to be concentrated in the proximal tubular cells. Several reviews of the role of transporters in renal excretion have been written 3—5. A summary of this material is presented below. The two transporter systems can work together to facilitate tubular secretion and the excretion of drugs. The uptake transporters initiate the process and move the drug from the blood into the renal tubular membrane.

The efflux transporters can then conclude tubular secretion by carrying the drug into the tubule. The tubular secretion of both fexofenadine, which is a substrate for renal OAT3 and P-gp 6, 7 , and that of adefovir, which is a substrate for OAT1 and MRP4, appears to be brought about in this manner. There is some overlap in the substrate specificity of the OATs, but OAT1 appears to be more important for small molecular mass drugs such as adefovir, and OAT3 appears to be more important for larger drugs such as the penicillin G and for sulfate and glucoronide conjugates such as estradiol glucoronide.

OAT3 can also carry positively charged molecules, such as the H2-receptor antagonists famotidine , and molecules with both positive and negative charges, such as fexofenadine. The high drug concentrations in the renal tubular cells produced by uptake transporters have been implicated in promoting the renal toxicity of drugs, such as adefovir, cidofovir, and cephaloridine.

This raises the possibility that the renal toxicity of these drugs could be reduced by the coadministration of inhibitors of the OAT transporters, such as probenecid.

These transporters promote excretion by transporting drugs from the blood into the tubular cells. The efflux transporters E , permeability glycoprotein P-gp and multidrug resistance—associated protein family MRP2 and MRP4 can conclude the process by transporting drugs from the tubular cells into the tubule. Substrates for OCT2 include the H2 antagonists cimetidine, famotidine , cisplatin, and metformin, which is almost completely eliminated by renal excretion.