Chapter 17 Metabolism

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Hepatic Clearance

The systemic or total body clearance clearance, CL, is a measure of the efficiency with which a drug is irreversibly removed from the body. One important component of this total body clearance is liver or hepatic clearance, CL_H. There are a number of models used to describe hepatic clearance including the venous equilibration model. This model include a number of parameters which can be considered in the understanding of hepatic clearance and liver disease or altered physiological state.

Venous equilibration model equation

We can consider the organ clearance as it may be measured in an isolated organ system. Here we would have for example an isolated liver, perfused with blood containing the drug of interest. By measuring the drug concentration in the blood entering and leaving the organ at steady state, the organ clearance can be measured directly for the drug.

Diagram 17.4.1 Blood Flow through the Liver

In Diagram 17.4.1, Q_H is the blood flow rate to the organ, C_A is the concentration of drug in the blood entering the organ, and C_V is the concentration of drug in the blood leaving the organ. The term E is the steady state extraction ratio. High E values mean high clearance by the liver and thus extensive metabolism.

The sum of the individual organ clearance values are equal to the systemic clearance, CL. For a drug which is eliminated entirely via the liver, the hepatic clearance is equal to the systemic or total body clearance. From the equation above we can see that the organ clearance is a function of the liver blood flow and the extraction ratio of the drug. The liver blood flow is a physiological parameter which may be altered in disease states. The extraction ratio, we shall see shortly is a parameter dependent not only of the condition of the liver but also the drug.

Both the hepatic clearance and the extraction ratio are empirical parameters which can be used as measures of the efficiency of the elimination process. They are dependent on three independent variables:-

total hepatic blood flow (Q_H),
fraction unbound (f_U) or the extent of drug binding to blood constituents. This may be saturable with high dose, polar compounds, and
the free intrinsic clearance (CL_int) or the rate-limiting step in drug uptake from blood, intracellular transport, metabolism, and where necessary biliary secretion. The free intrinsic clearance may be thought of as the clearance of drug from liver plasma water, devoid of the influence of blood flow or binding. Since a major part of this parameter is metabolism which is typically enzyme mediated this parameter may be saturated at higher doses, for some drugs

The equation describing hepatic clearance in terms of these parameters using the venous equilibration model can be defined as (Wilkinson and Shand 1975):-

Equation 17.4.1 Hepatic Clearance

With this equation it is possible to look at the influence of free intrinsic clearance, drug binding, and liver blood flow on the overall hepatic clearance of a drug using applets calculating plasma concentrations after iv bolus or oral dosing.

Drugs can be classified into three types depending on the intrinsic clearance and binding. Flow limited, capacity limited, and others.

Flow limited drugs

High f_U • CL_int (= CL^total_int) value. [f_U • CL_int >> Q_H]. For drugs with high total intrinsic clearance the extraction ratio, E, approaches 100%, the hepatic clearance approximates and is dependent of hepatic blood flow. Hepatic clearance is said to be FLOW LIMITED. Also, we can note that the hepatic clearance is not dependent on moderate changes in free intrinsic clearance or binding to blood constituents.

Examples include:- lidocaine, propranolol, morphine.

Capacity limited drugs

Very low total intrinsic clearance. [f_U • CL_int << Q_H]. With drugs having very low intrinsic clearance, hepatic extraction is inefficient and hepatic clearance becomes independent of hepatic blood flow. Now changes in free intrinsic clearance and/or binding to blood constituents becomes very important in determination of the overall hepatic clearance. Hepatic clearance is said to be CAPACITY LIMITED as the intrinsic capacity of the liver controls the drug clearance.

Examples include:- phenytoin, warfarin, and quinidine. For such drugs it is possible that liver disease will cause a decrease in CL_int but also an increase in fu. In this case the overall hepatic clearance doesn't reflect just the hepatic metabolic activity but also the drug binding. This is illustrated with tolbutamide. In patients with hepatitis there is an increase in fu but no change in CL_int. As a result CL is increased and the elimination half-life decreases. The change in elimination half-life reflects changes in binding and not changes in drug metabolizing activity.

Other drugs

Between these two extremes. Capacity-limited but binding-insensitive drugs. The three parameters; Q_H, f_U, and CL_int are important determinants of drug elimination.

Examples include:- theophylline, antipyrine

There are other models for liver metabolism besides the well-stirred (venous equilbration) model described above, such as the parallel-tube (sinusoidal perfusion) and the dispersion model. Explore the well-stirred and parallel-tube models after IV administration and oral administration as interactive graphs.

As a reminder explore the relationship between extraction ratio, blood flow, clearance, apparent volume of distribution, half-life and elimination rate constant.

Figure 17.4.1 Clearance, V, kel and t_1/2

Click on the figure to view the interactive graph

References

Wilkinson, G.R., and Shand, D.G. 1975 A physiological approach to hepatic drug clearance, Clin. Pharmacol. Ther., 18, 377-90

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