Hepatic clearance, CLh

From either a Cp or In Cp versus time plot, one feature is immediately clear the drug concentration drops over time. This process is called elimination and is determined by clearance (CL). Clearance is the process of removal of drug from the bloodstream. As was discussed in Chapter 3, clearance occurs primarily either through filtration of a drug by the kidneys (renal clearance, CLR) or metabolism of a drug in the liver by the action of enzymes (hepatic clearance, CLH). Other clearance processes are possible, but CLR and CLh normally comprise the large majority of total clearance (CLy or simply CL) (Equation 7.6). 

Hepatic clearance (CLH) can be crudely approximated from bioavailability (F) according to Equation 7.34. 

Due to its mathematical simplicity, most in vitro-in vivo correlations are based on a homogeneous, well-stirred model for the liver such that all metabolic enzymes in the liver are exposed to the same drug concentration [266]. Under steady-state conditions, the predicted hepatic clearance CLh for this model is... 

Hepatic clearance (CLh) may be defined as the volume of blood perfusing the liver that is cleared of drug per unit time. Usually, hepatic clearance is equated with nonrenal clearance and is calculated as total body clearance (CLe) minus renal clearance (CLr) ... 

Clearance is referenced to plasma (plasma clearance, CLp), blood (blood clearance, CLb) or plasma water (unbound clearance, CLu), depending upon where the concentration is measured. Total clearance can be divided into the contributions of each of the eliminating organs, the most important being renal clearance, CLr, and hepatic clearance, CLh. 

The hepatic extraction ratio (ERh) can be determined after intravenous dosing from the ratio of hepatic clearance (CLh) to hepatic blood flow (2h)-... 

One fact that can be observed from this limiting-case analysis is that no matter how much intrinsic enzyme activity is present in the liver, the hepatic clearance (CLh) can never be greater than the hepatic blood flow rate ( ()h). ... 

In vivo Prediction Hepatic clearance (CLh) in the well-stirred model can be expressed as... 

If the rate of elimination decreases in Scheme 7.2, then what happens to clearance Clearance is unchanged. For each 4.0-second pass, the liver clears 50 mL (CLh = 12.5 mL/s) out of the total 100 mL of blood that flows through the organ. Literally, 50% of the blood volume is cleared, so the actual impact is a decrease in Cp by 50%. While clearance is constant, the effect of clearance on Cp varies with Cp. Clearance depends on the action of metabolic enzymes on the drug and, at very high drug concentrations, the enzymes can become saturated with substrate. Under these conditions, which are rare, clearance is not constant. Therapeutic concentrations of modem drugs are normally well below the concentrations required to saturate liver enzymes. The tubular secretion and reabsorption processes in the kidneys can also be saturated and affect renal clearance. As with hepatic clearance, variable renal clearance is rare. 

At this point, the standard equation for hepatic clearance (see Equations 9.9 and 9.12) is used to convert CLillt to in vivo human clearance (CLH(Caic)) ... 

CL can be easily converted to a more meaningful number called blood-flow-normalized CL that reflects the elimination efficiency. This is related to the notion that CL is a flow that takes a compound out of the systemic circulation. For example, the maximum liver clearance should not exceed the liver blood flow, since the clearing rate cannot exceed the delivery rate. The value of liver clearance is therefore more meaningful when compared to its blood flow as expressed by the extraction ratio E = CLh/gh, where CLh is hepatic clearance and Qh is hepatic blood flow. Typically, the liver is the major organ for elimination. Liver has a relatively... 

The extent to which the liver successfully eliminates a xenobiotic from the blood is determined by the intrinsic clearance of the liver (Clh) and the rate at which the xenobiotic is presented to it (i.e., the hepatic blood flow Qh ). This gives the overall hepatic extraction ratio (E) for the compound, as shown in Equation 11.3 ... 

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