Clearance Rate As An Expression Of Drug Elimination Rate

A clearance rate is defined as the volume of blood or plasma completely cleared of drug per unit time. It is a useful way to describe drug elimination because it is related to blood or plasma perfusion of various organs of elimination, and it can be directly related to the physiologic function of these organs. For example, the renal clearance rate (RCR) of a drug can be calculated using the following equation:

Amount excreted in urine per unit time

Plasma concentration

Example. In the example plotted in Figure 6, the amount of drug excreted over the 0- to 0.5-hour interval was 37.5 mg. If the plasma concentration at 0.25 hour (the middle of the interval) was 10 mg/mL, what was the RCR? From equation (18),

100 mg/mL

= 125mL/min

The glomerular filtration rate (GFR) in normal males is estimated to be 125 mL/min, and the results of the example calculation suggest that the drug is cleared by GFR. If the RCR had been less than 125 mL/min, tubular reabsorption of the drug would have been suspected. Had it been greater than 125 mL/min, tubular secretion would have been involved in the drug elimination.

Drugs can be cleared from the body by metabolism as well as renal excretion, and when this occurs, it is not possible to measure directly the amount cleared by metabolism. However, the total clearance rate (TCR), or total body clearance, of the drug can be calculated from the total amount administered (dose) and "total" concentration, area under the plasma concentration versus time curve (AUC) (see sect. "Area under the Plasma Concentration versus Time Curve") using the following equation.

Dose

Example. One hundred milligram of drug was given IV to a patient, and plasma concentrations were measured. The AUC was determined to be 87 mg.min/L. Calculate the TCR of the drug.

When a drug is eliminated by both metabolism and urinary excretion, it is possible to calculate the metabolic clearance rate (MCR) by the difference between TCR and RCR:

The RCR can be determined from urine and plasma data using equation (18), and the TCR can be determined using equation (19). Alternately, the RCR can be calculated by multiplying the TCR by the fraction of the dose excreted unchanged into urine, fe:

If it is assumed that the fraction of the dose not appearing as unchanged drug in urine has been metabolized, the MCR can be calculated as follows:

Example. An IV dose of 250-mg was given to a normal volunteer. The measured AUC was 289 mg.hr/L, and 60% of the dose was recovered as unchanged drug in urine. Calculate TCR, RCR, and MCR for the drug in this person.

250 mg

It should be emphasized that the assumption that any drug not appearing as unchanged drug in urine has been metabolized may introduce a great amount of error into the values of the clearance rates estimated using equations (21) and (22). By this assumption, unchanged drug eliminated in the feces would be included with metabolized drug, as would any orally administered drug that was unabsorbed.

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