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.

      • Hala says:

        i want to ask a question why in non linear PK increasing dose lead t decrease in the CL although its supposed to remain constant.

        • Nathan Teuscher says:

          Thanks for the question. A drug that exhibits non-linear PK has a clearance that changes with dose by definition. The reasons that a drug exhibits non-linear PK vary greatly, but often the reasons are associated with saturating drug metabolism pathways.

  3. Alex says:

    Hi,
    After reading the section on primary and secondary PK parameters, I was wondering if you could clarify some points related to clearance.

    -Based on CL = ln 2 x Vd / T1/2, it would seem that clearance is proportional to the Vd. Given that this formula includes primary (vd) and secondary (T1/2) parameters, would it be false to say so? I assume clearance and Vd are independent, physiologic parameters.
    -Can we say that T1/2 plays a significant role regarding clearance?

    -I’ve read that clearance is independent of the total dose administred. Would it still be true in a one-compartment model? I would say yes, as long as we are dealing with first order kinetics. What if we are dealing with zero-order kinetics, where total dose could saturate metabolism or excretion, wouldn’t clearance then depend on the total dose administred? Can we still talk about clearance in zero order kinetics, or do we have to talk about the rate of elimination?

    Thank you for your time

    • Nathan Teuscher says:

      Alex,

      The notion of “primary” and “secondary” parameters is based on physiology and chemistry rather than equations. Using equations and noncompartmental techniques, we can create any number of relationships and then say that the parameters on the left depend upon the parameters on the right. The equation you presented for CL simply substitutes ln 2/T1/2 for kel. So I wouldn’t try to draw any conclusions about dependency from that single equation.

      Clearance is a function of the efficiency with which the body removed drug from the systemic circulation. This can be the liver, lungs, kidney, or other tissues and organs in the body. Volume of distribution is a theoretical proportionality parameter that relates the amount of drug in the body to the concentration measured in some biological fluid. Parameters such as T1/2 are simply derived from the primary parameters CL and V. So it would be incorrect to say that T1/2 plays a significant role in clearance. Instead, you can say that as CL decreases, T1/2 increases because T1/2 is derived from clearance.

      For drugs that exhibit linear pharmacokinetics, clearance is independent of the dose administered. This can be true for any compartmental model. If however, a drug exhibits non-linear pharmacokinetics (e.g., saturable metabolism), then clearance is not independent of the administered dose. So as you indicated if we have saturable elimination kinetics, then we need to identify the equation that describes clearance rather than a specific value for clearance.

      Best regards,
      Nathan

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