What does Clearance mean?

Drug clearance is an extremely important topic in the science of pharmacokinetics. Drug clearance defines how much drug should be administered, how frequently to dose a patient, and how two interacting drugs will affect a patient. The primary PK parameter clearance is very similar to it’s friend, volume of distribution. Clearance (CL) is a proportionality factor that relates the concentration of drug measured in the body to the rate of elimination. In mathematical terms:

Rate of Elimination = CL * C(t)

In most cases, CL is considered to be constant (Red line). This means that the rate of elimination (Green line) changes in direct proportion to the concentration of drug measured (Blue line). This concept is illustrated in the following graph:

Some might ask, what does it mean to “clear” a drug. Clearance is a collection of processes by which the body removed the drug from the body. This occurs in two general ways.
Metabolism – Drug can be metabolized, or converted into other chemical species.
Elimination – Drug is removed from the body by a specific organ (e.g. kidneys)

When either metabolism or elimination occur, the drug is no longer available to cause a pharmacological effect in the body. Metabolism often takes place in the liver. The liver is full of enzymes such as the cytochrome P450s which convert the drug into more hydrophobic hydrophilic species which can then be eliminated. Elimination occurs when the drug is removed from the blood or plasma and placed “outside” of the body. The kidney is an elimination organ. The kidneys take drugs from the blood and move them to the urine.

In some cases, the clearance of the drug changes with the concentration of drug measured in the body. This situation is called non-linear clearance, or non-linear pharmacokinetics. Often this occurs when elimination or metabolism is controlled by a single enzymatic pathway that can get saturated.

In summary, clearance is a proportionality factor, just like volume of distribution. Clearance relates the rate of elimination to the concentration measured in the body. Clearance is a function of organ function, and efficiency and is different for each drug.

Comments

  1. nikunja says:

    How to obtain clearance for non-linear pharmacokinetics?
    I have found different relations in different articles and books {i.e. Cl= (Vmax )/(Km+C ) and somewhere Cl=(Vmax C)/(Km+C)}.
    what is its role in non- linear pharmacokinetics?

    • Nathan Teuscher says:

      Nikunja,

      Excellent question, thank you for opening a discussion on this topic. Non-linear pharmacokinetics occurs when the clearance of a drug changes with the amount of drug given. Thus it would be more appropriate to call it non-linear clearance pharmacokinetics. The equation for clearance is always the same: CL=Dose/AUC. But in non-linear PK, the value for CL is not constant across different doses. As you increase Dose, clearance decreases resulting in AUC values that are higher than would be predicted under linear PK (and constant CL). If you know that non-linearity in clearance (e.g. how CL changes with dose), then you can develop an equation for calculating the CL. One of the equations you wrote (2nd one) is accurate for a saturable clearance process (e.g. saturating an enzyme): CL=(Vmax*C)/(Km+C) where C is the plasma concentration. Other equations can also be used … it depends on what causes the changes in clearance with different drug concentrations. You can read more about non-linear PK here.

  2. Punna Rao Ravi says:

    Dear Dr. Nathan,
    I have two queries for which i need your help
    1. I think there is some mistake in the sentence ‘The liver is full of enzymes such as the cytochrome P450s which convert the drug into more hydrophobic species which can then be eliminated. Elimination occurs when the drug is removed from the blood or plasma and placed “outside” of the body.”
    Enzymes convert the drug into hydrophilic species which are readily excreted. Except in some case where there are converted to more hydrophobic species (methylation etc).
    2. I would like to know why do we classify Vd and Cl as primary parameters and T1/2 or Ke as secondary parameters. We determine the Ke (for IV bolus one compart) from the slope of Log C vs T plot. So in that sense Ke is determined directly and it is not derived from other parameter.
    So clarify.
    Thank you

    • Nathan Teuscher says:

      Thank you for your comments. I have corrected the sentence you noted in comment #1. Thanks!
      Regarding your question about primary and secondary PK parameters, the designation does not come from how a parameter is calculated, rather it comes from the relationship to physiology. You suggest that the elimination rate constant is a primary parameter because it can be determined from the concentration-time data. While that is one way to determine the parameter,using that same concentration-time data, I could derive V and CL and calculate Ke using Ke=CL/V. So I believe that the designation of primary is independent of the calculation method. Volume and Clearance are directly related to physiology. Half-life and elimination rate constant are derived from the physiology-related parameters. For example, as we age, our livers become less efficient, thus clearance decreases. This decrease is directly related to the ability of the body to metabolize and remove drug. As clearance decreases, many times the elimination rate constant decreases and the half-life increases. As we age, some people also lose weight. The reduction in weight may decrease the volume of distribution for certain drugs. Thus with ageing, we can see a decrease in clearance and a decrease in volume of distribution. In this specific scenario, the elimination rate constant and half-life would stay constant. Thus, the concentration-time curves for an ageing patient and a young volunteer may have the same half-life (i.e., terminal slope), but they will not be superimposeable. Thus, I believe V and CL to be primary PK parameters because they are tied to physiologic concepts.

Trackbacks

  1. [...] and Your Pay Stub Bioavailability is another primary pharmacokinetic parameter (like Clearance and Volume of Distribution) that describes the fraction of administered drug that reaches the [...]

Speak Your Mind

*

* Copy This Password *

* Type Or Paste Password Here *