Hepatic Clearance


Key Terms:


Unbound intrinsic hepatic clearance (CLuint): The ability of the liver to remove drug from the blood in the absence of other confounding factors (such as blood flow and protein binding). CLuint is a function of enzyme activity or biliary excretion.


Systemic availability: The fraction of administered drug that reaches the systemic circulation. Commonly used to measure the extent to which drug is available in the body after non-intravenous administration.


Key Principles:


Venous equilibrium model of hepatic clearance. Elementary models of organ clearance would indicate that CLH = QHE. However, studies with perfused liver preparations readily revealed that E was not independent of QH. Thus, a more complex model is necessary to characterize hepatic drug clearance in terms of independent, non-interacting variables. Of the models proposed, the venous equilibrium model is the most simplistic model that accurately predicts changes in drug concentration as a function of blood flow, protein binding, and enzyme activity. The model assumes that blood exiting the liver in the hepatic vein is in equilibrium with the blood that is bathing the sinusoids in the liver (Hence the name, venous equilibrium).


Perfusion rate-limited elimination. Drugs with a high hepatic intrinsic clearance are removed from blood essentially as rapidly as they can be delivered to the liver. Therefore, the elimination of such drugs is highly dependent upon liver blood flow. Such drugs are said to exhibit perfusion rate-limited elimination. Examples of such drugs would be propranolol and verapamil.


Restrictive clearance. For drugs that exhibit a low intrinsic clearance,  CLH ~ fubCLuint.  Thus, the hepatic clearance of such drugs is dependent upon protein binding and enzyme activity. For these drugs, protein binding ‘restricts’ their metabolism … such that only unbound drug is eliminated with each pass through the liver. Thus, they are said to exhibit restrictive clearance. Examples of such drugs would be diazepam and warfarin. On the other hand, some drugs are metabolized so rapidly by the liver they are said to exhibit non-restrictive clearance. In other words, their elimination is such that protein binding does not act as a significant determinant in their elimination (CLH ~ QH). Propranolol would be a good example of such a drug.


Changes in total drug concentration do not always necessitate changes in the dosage regimen. While drug interactions at the level of protein binding are easily demonstrated for many drugs, these changes are often clinically insignificant. Since it is the unbound (or free) drug that is pharmacologically active, our real concern is what happens to the free concentration of drug. For drugs that exhibit a low intrinsic clearance, changes in the free fraction will not effect the steady-state concentration of free drug (after either or intravenous administration). Therefore, displacement of a low intrinsic clearance drug from protein binding sites will result in a decrease in the total drug concentration, but no change in the free concentration. For this reason, protein binding interactions with low intrinsic clearance drugs would not be expected to be clinically important. What is important is how we interpret changes in total drug concentration that may occur. This is especially important to recognize since many, if not most, clinical labs measure only total drug concentration. Based on total drug concentration alone, one could be mislead into thinking a change in therapy was needed as a consequence of the addition of a protein binding displacer to a patient’s therapeutic regimen. However, since the free drug concentration will not change, changes in the total drug concentration are inconsequential.


Practice Problems:


1.         Below is shown the plasma concentration versus time curve after intravenous and oral administration of diazepam. Draw the anticipated curve for diazepam after each route of administration if this patient were pre-treated with cimetidine.  Answer


                                         Intravenous                                                                          Oral






2.      DJ is a 40 year old male who is receiving valproic acid for the prophylactic treatment of migraine headaches. While the drug has effectively reduced the frequency and severity of his headaches, he continues to experience one or two severe episodes monthly. DJ has been asked to participate in a clinical trial of a new drug that would be added to his regimen of valproic acid. Studies in vitro show that this investigational drug can displace valproic acid from plasma protein binding sites. Below are the average pharmacokinetic parameters for valproic acid in adults.



Average Values


10 ml/hr/kg


0.20 L/kg

% of drug excreted in urine as


Parent drug







14 hrs


            Based upon this data, what would you predict would happen to the total and free steady-state concentration of valproic acid when the investigation drug is added to this patient’s regimen?





Last revised 07/13/05


ã 2005 - Craig K. Svensson, Pharm.D., Ph.D.


Return to the Index for Lecture Tutorials


Return to Pharmacokinetics and Biopharmaceutics Homepage