Clearance

This chapter answers parts from Section B(iv) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the mechanisms of drug clearance and metabolism." As such, it comes closest to the learning objective of this syllabus section, that being "an understanding of the fate of drugs in the body". The college has interrogated this extensively. They seem particularly fond of renal clearance mechanisms, as this has come up three times in the past written papers. Overall, clearance topics seem to be an issue of interest. The time-poor exam candidate in the grip of some sort of frothing eleventh-hour cram frenzy might find their precious minutes better spent on revising this topic instead of something like "gastric drug absorption".

The mechanisms of drug clearance and metabolism are a pretty general description for some complex processes, but it is possible to summarise them all into a few memorable sound bites. In brief :

• Clearance is the efficiency of irreversible elimination of a drug.
• Clearance is defined as 'the volume of blood cleared of drug per unit time'.
• It is the proportionality constant between plasma drug concentration and elimination rate.
• Drug elimination rate is defined as 'the amount of drug cleared from the blood per unit time'
• In first order kinetics, elimination rate is proportional to dose, while clearance rate remains independent of the dose. 
• In zero-order kinetics, elimination rate is constant.

The official college pharmacology text  (Birkett et al, Pharmacokinetics Made Easy - 2009) goes right to the heart of the matter in Chapter 1 ("Clearance", p. 18). This four-page chapter in itself is probably enough to pass the exam, considering especially that the generic concepts of clearance have never been asked about specifically (i.e. at no stage has any trainee been asked "what is clearance? Define the term", etc). If this chapter does not seem to fill the lonely void of need, the time-rich trainee can satisfy themselves in the extensive Basic Pharmacokinetics by Jambhekar and Breen (2nd ed, 2009) - this textbook dedicates a substantial amount of space to matters of clearance, with a special focus on renal excretion (Chapter 4,"Clearance concepts" - p. 53-77). For some primary sources, one may wish to read Malcolm Rowland's Clearance concepts in pharmacokinetics (1973) if you can get a hold of a free copy. To help unravel the concept of clearance from the (completely distinct) concept of elimination, a reader has recommended Chiou (1982) and Mehvar (2018), of which the latter is available as free full text, but which was described as "intimidating" by a professional university-affiliated pharmacology researcher. A better option might be "A Short Introduction to Pharmacokinetics" by Urso Blardi & Giorgi (2002), where clearance takes centre stage on page 41.

Definition of clearance.

According to Birkett (2009), the official definition of clearance is as follows:

"Clearance" describes the efficiency of irreversible elimination of a drug from the systemic circulation. 

Clearance is defined as 'the volume of blood cleared of drug per unit time'.

As a one-liner, that's pretty good. Other definitions are possible. For instance, clearance is not always about clearing a volume of blood (what about plasma?).  Unfortunately definitions which encompass these subtleties tend to overgrow with subclauses and become so cumbersome and verbose as to become unusable for exam preparation. For instance, Jambhekar and Breen (2009) offer the following:

The most general definition of clearance is that it is ‘‘a proportionality constant describing the relationship between a substance’s rate of elimination (amount per unit time) at a given time and its corresponding concentration in an appropriate fluid at that time.’

...Clearance can also be defined as ‘‘the hypothetical volume of blood (plasma or serum) or other biological fluids from which the drug is totally and irreversibly removed per unit time."

Now, regarding "the fate of drugs in the body". Generally speaking, there are only two possible fates. A drug can be excreted (i.e. removed from the body in an unchanged form) or it can undergo biotransformation into something chemically distinct. In either case, its is cleared and eliminated.

Drug clearance vs. drug elimination

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. Applied Biopharmaceutics & Pharmacokinetics (Shargel and Yu , 6th ed) defines elimination as the "irreversible removal of the drug from the body" and clearance as "volume of fluid cleared of drug per unit time". 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. 

Elimination rate can be described by the equation, 

The equation can be rearranged to solve for clearance.

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. Both have a clearance value of around 600-800ml/min. However, felodipine has a much larger volume of distribution (3-4 times) and therefore its elimination half-life is prolonged (also by three to four times).

Total body clearance and organ-specific clearance

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.

• Systemic clearance (Cl_s) which is the sum of all clearances
• Renal clearance (Cl_r) - the fraction of total clearance which is handled by the kidneys
• Metabolic clearance (Cl_m)  - the fraction of total clearance which is the consequence of drug biotransformation, by whatever mechanisms
• Hepatic clearance (Cl_H) - the fraction of total clearance which is handled by the liver, regardless whether this is by biliary excretion or by metabolism
• Intrinsic clearance (Cl_int) - the hepatic clearance a drug would have if it was not restricted by hepatic blood flow rate
• Intrinsic unbound clearance (Cl'_int) - the intrinsic clearance a drug would have in the absence of plasma protein binding.

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). Because of this, usually clearance is divided into just two subsets: renal and non-renal (Cl_r and Cl_nr).

Extraction ratio

The clearance performance of an organ can be described in terms of extraction ratio which is a dimensionless term that describes the proportion of the substance removed from the blood by the act of being filtered through abovementioned organ. This dimensionless term is unimaginatively referred to as E.

This ratio is expressed as a fraction or percentage. If one knows the extraction ratio of an organ and the blood flow to that organ, one can estimate the contribution it makes to the total drug elimination from the body.

Calculation of clearance

You can either try to calculate clearance on the basis of elimination (by observing the drug concentration diminishing in the plasma) or by picking an organ and measuring its ability to excrete the drug. Renal clearance is easy to measure in this fashion. Collect the patient's urine in measured time increments, record its volume, and compare the blood concentration to the urinary concentration.

If you do not wish to analyse buckets of urine, the alternative is to collect blood samples at known intervals and relate the drug concentration to the administered dose.

Thus: 

The relevance of clearance to maintenance dose calculations

At a very basic level, if you wanted to maintain a certain concentration of drug in the plasma, your dose rate calculation would look like this:

Pretty straightforward. Dose of drug going into the patient is matched to the dose of drug coming out. Elimination rate may not always be available, but one is usually able to have a plasma drug concentration. The maintenance dose can then be calculated from the clearance rate and plasma concentration: