Pharmacokinetics/Pharmacodynamics

the liver per unit of time. The ability of the liver to metabolize drugs depends on three physiologic variables:

hepatic blood flow, drug protein binding, and the intrinsic activity of hepatic enzymes. When evaluating an

intravenously administered drug (bioavailability of 1), clearance by the liver can be simply represented by

the following equation:

CLH = Q × E

where CLH is the hepatic clearance, Q is the hepatic blood flow, and E is the hepatic extraction ratio. The

hepatic extraction ratio can further be described by the following equation:

E =

fu × CLint

Q + fu × CLint

where fu is the fraction unbound in the plasma, CLint is the intrinsic hepatic clearance, and Q is hepatic blood

flow. The hepatic extraction ratio is classified by the fraction of drug removed during one pass through the

liver and can range from 0 to 1. It can be separated into high (greater than 0.7), intermediate (0.3–0.7), and

low (less than 0.3) categories. The extraction ratio would be zero when the liver does not metabolize a drug

and 1 when CLH depends entirely on hepatic blood flow. The effect of changes in critical illness depends

on the extraction ratio of the drug. Table 1 lists select high extraction ratio and low extraction ratio drugs.

Drugs with a high hepatic extraction ratio are metabolized by hepatic enzymes and are thus cleared by

the liver. In drugs with high extraction ratios, clearance does not vary with changes in hepatic enzymatic

activity and is primarily limited by hepatic blood flow. Mathematically, this can be represented by:

fu × CLint>>>Q

Given the previously stated relationship, CLH can be simplified to:

CLH = Q

As previously noted, clearance of a drug pertains to removal of the drug from the blood. Therefore, the

effect on plasma drug concentration will affect the efficacy of the drug. Because an unbound or “free

drug” elicits the pharmacological response, the unbound steady-state concentration (Cssu) is important

to assess. The total concentration, otherwise called the steady-state concentration (Css) of hepatically

metabolized drugs, can be represented by the following equation:

Css = dose

CLH

where Css is the steady-state concentration (for both protein bound and unbound drugs) and dose is the

rate of drug input. Because CLH = Q for high extraction ratio drugs, the equation can be modified to:

Css = dose

Q

The unbound steady-state concentration for a high extraction ratio is represented by the following

equation:

Cssu = fu × dose

Q