Now that the basic concepts of volume of distribution and the elimination rate constant have been introduced, we can start talking about one of the more challenging but certainly one of the most important concepts of pharmacokinetics – drug clearance. Secondly, it’s worth prefacing that this article assumes that readers have a basic knowledge of renal physiology.
Why is drug clearance important?
Clinically, the single most important use of drug clearance is to calculate what is referred to as the maintenance dose. A maintenance dose is the dose of a drug (typically given in milligrams or smaller units) that needs to be administered to an individual to achieve a desired steady-state concentration (Css) in the blood plasma. In other words, by knowing how a desired concentration of a drug (the Css, which is the region of plasma concentrations that provide a therapeutic effect) gets cleared from the system (quantified by clearance), one can determine the dose of a drug that needs to be administered to attain that desired concentration. Indeed, the volume of distribution of a drug will determine the attained concentration in plasma as it estimates the apparent volume that administered dose is ‘dissolving’ in. It is important to note that in this example, the route of administration is considered to be intravenous infusion.
These desired steady-state concentrations lie within a so-called therapeutic range, i.e. plasma concentrations ranging from the minimum concentration that produced an objectively measured pharmacological effect and the maximum concentration that still produced that effect and still avoided intolerable side effects. Practically, this therefore means that if a clinician is about to administer a dose of a given drug, they need to be sure that a patient’s ability to clear the drug is not impaired or enhanced, otherwise they are risking that the attained plasma concentration will be outside the therapeutic range. These concepts are summarised in Figure 1.
Figure 1: The importance of clearance. The drug output measured by total drug clearance can be used to calculate the maintenance dose that needs to be given (in this case by continuous IV infusion) to attain desired steady-state plasma concentration within a therapeutic range.
What is drug clearance?
So what actually is clearance? The definition of clearance is the rate of drug elimination from the body with respect to the drug’ concentration in plasma. However, this is a rather confusing definition so let me, instead of using this definition, attempt to simplify it.
First of all, it is important to define drug elimination: it is the irreversible loss of drug from the body. That essentially means the drug, i.e. the chemical compound that was administered, is no longer present in the system. This can therefore happen in two ways that are related: by drug metabolism and excretion. Indeed, when a drug is metabolised, it is converted to a different chemical compound by enzymatic processes. Vast majority of metabolism takes place in the liver by so-called Cytochrome P450 (CYP450) enzymes, but it may also happen in other organs. The full explanation of how drugs get metabolised is not a scope of this article and will therefore be discussed elsewhere.
Drug excretion is the removal of either an unchanged drug or its metabolite from the body, and this mainly happens via the kidneys, the hepatobiliary system (in faeces) or the lungs (very important for gaseous anaesthetics). Typically, lipophilic drugs are the ones that are not easily excreted unchanged by the kidneys as they distribute well into tissues, and therefore are the ones that first need to be metabolised to more polar substances by the CYP450 system. Drugs such as furosemide, methotrexate or gentamicin are excreted largely in their unchanged forms.
It is now important to stress one crucial point. Drug elimination rate is the amount i.e. the grams, milligrams or micrograms, that get removed from the body per unit of time, for example mg/h. In fact, same units would be used for drug input, such as constant intravenous infusion rate. Any drug administered into the body then forms a concentration in the plasma where it is sampled, and that is why clearance is a better measure of drug elimination than drug excretion itself! This is because clearance normalises drug excretion rate to plasma concentration, which is crucial because the concentration of a drug in plasma first needs to be physically delivered to the target organ excreting the drug.
Let us take a drug X to illustrate this point. If 5mg of a polar drug X, which is known to be eliminated unchanged via the kidneys, is administered intravenously and plasma sampling reveals that plasma concentration 1 μg/mL and the rate of drug elimination by the kidneys is determined to be 200 μg/min by measuring the amount of the drug in the urine, then the drug clearance will be 200 mL/min. This means that only 200 mL of the plasma containing the 1 μg/mL concentration had been physically delivered to the kidneys in 1 minute, that is, only 200 mL of plasma was cleared of the drug in a unit of time. This is, in fact, another way how one can define clearance: the volume of plasma a drug is dissolved in fully cleared of the given drug per unit of time. This is illustrated in Figure 2.
As the glomerular filtration rate of healthy kidneys is generally quoted as 125 mL/min, this result would also imply that some of the drug gets secreted into the kidney, rather than just being filtered at the glomerulus – an important piece of information to consider as co-administering another agent that gets secreted into the tubular system by the same mechanism would impact the clearance, and thus plasma concentration of the first drug.
Figure 2: Illustration of clearance via the kidneys. 5 mg of Drug X is administered intravenously and reaches the kidneys with plasma concentration of 1μg/mL. Urine collection shows that 12 mg of drug was collected in 1 hour, therefore 200 μg are eliminated every minute. Clearance can be calculated using the given formula, and is found to be 200 mL/min. This implies both filtration and secretion of drug X into the tubular system of the kidney. Please note that this schematic is assuming no drug reabsorption from the tubular system.
At the aforementioned steady-state, the rate of drug input into the body (in for example mg/h) is equal to the rate of elimination. Therefore, the equation in Figure 2 can be rearranged as Clearance = rate of drug infusion/plasma concentration (now at steady-state) where plasma concentration at steady-state, the Css, is obtained by regular blood sampling. Hopefully, you can now appreciate that knowing the clearance thus allows clinicians to decide on the dosing rate that is needed to achieve a particular Css. Indeed, clearance can also be estimated from other routes of administration but that will be discussed in future articles.
Hepatic drug clearance and the extraction ratio
It is important to now introduce the concept of extraction ratio and I will do so together with outlining what is meant by hepatic clearance.
As I have outlined above, the main enzymes responsible for drug metabolism are CYP450 enzymes located in the liver. Drug metabolism, together with excretion, is a process responsible for drug elimination as the drug is chemically changed, typically to a more polar substance. Naturally, in order for a drug to get metabolised in the liver, it first needs to be delivered to the organ in the blood plasma. Every minute, a liver in a healthy adult is receiving about 1-1.5L of plasma, and therefore, every minute there is a theoretical chance of clearing 1-1.5L of plasma free of the drug, i.e. the maximum hepatic clearance is theoretically equal to the blood flow to the liver.
However, the organ’s ability to remove or extract the drug from the plasma, i.e. the extraction ratio (ER), needs to be taken into account, and is therefore often measured in the drug development process. The ER is the fraction of a drug removed by the organ and is calculated by sampling concentrations of the drug entering the organ (Cin) and leaving the organ (Cout). This is schematically illustrated in Figure 3. Indeed, hepatic clearance will be equal to the product of liver blood flow and the extraction ratio for a given drug.
Figure 3: Extraction Ratio. In the case of high ER, the liver has a high ability to extract the drug from the blood causing a large difference between Cin and Cout. On the other hand, a small difference between those to concentrations leads to a smaller ER. Hepatic clearance will be equal to the product of hepatic blood flow (1-1.5 L/min) and the extraction ratio for a given drug.
For example, the calcium-channel blocker verapamil has an extraction ratio of 0.9, and is therefore readily metabolised by the liver. Its hepatic clearance, if hepatic blood flow is assumed to be 1.5 L/min, will therefore be approximately equal to 1.35 L/min. Indeed, the total clearance of a drug will be equal to the sum of its clearances due to individual organs.
Conclusion and looking ahead
Hopefully this article provided a short and convenient introduction to the concept of drug clearance. It’s also hoped that readers understand the relevance of this concept when designing dosing regimens. In the coming articles in this series, I will attempt to explain the different types of elimination kinetics as well as explaining the importance of concepts such as half-life and its link to the elimination constant, clearance, and volume of distribution.
Michal Barabas is currently a medical student at the University of Cambridge, where he also teaches pharmacology to undergraduates in small group seminars. Michal obtained a BSc. degree in Pharmacology from UCL in 2013 and an M. Phil degree in Translational Medicine from the University of Cambridge in 2014.