Transcript
0:00Metabolism, excretion and elimination
Lesson 5.1 of our excretion module: clearance. Metabolism is the chemical change of a drug by enzymes, and its products are metabolites. Excretion is the removal of the drug and its metabolites from the body, mainly in urine and in bile. Bile is a fluid that the liver secretes into the small intestine. Elimination is the irreversible loss of the drug from the body by metabolism and excretion. Plasma is the liquid part of the blood.
0:40What is clearance?
Clearance is the volume of plasma from which the body removes all of the drug per unit of time, for example in liters per hour. The body removes only the drug, and the plasma stays in the body. The rate of elimination, the amount of drug that the body removes per unit of time, equals the clearance times the plasma concentration. With a clearance of 52 liters per hour, the body removes 52 milligrams per hour at a concentration of 1 milligram per liter. At half that concentration, it removes 26 milligrams per hour. Transporters are proteins that carry drugs across cell membranes. The enzymes and transporters that eliminate a drug have a maximum rate. Well below this rate, clearance is independent of the concentration. Clearance therefore measures the ability of the body to eliminate the drug. This lesson describes clearance in three parts.
1:55Measuring clearance
The first is the measurement of clearance. An intravenous dose goes into a vein, so the whole dose enters the systemic circulation directly. Blood samples give the plasma concentration over time. The area under the whole concentration-time curve, the AUC, measures the total exposure to the drug. The body eliminates the whole dose, and the amount eliminated equals the clearance times the AUC. Clearance therefore equals the intravenous dose divided by the AUC. For an oral dose, the drug reaches the systemic circulation only after it passes through the gut wall and the liver. The oral bioavailability, F, is the fraction of the dose that reaches the systemic circulation unchanged. Only F times the dose enters the systemic circulation. The oral dose divided by the AUC therefore gives the clearance divided by F, the apparent oral clearance.
3:13Organ clearance
The second is the clearance of each organ. The kidneys excrete unchanged drug into urine, and their clearance is the renal clearance. The liver removes drug by metabolism and by excretion into bile, and its clearance is the hepatic clearance. An organ removes drug only from the blood that flows through it. Its blood flow therefore sets the upper limit of its blood clearance, the clearance based on the drug concentration in blood instead of plasma.
3:52Adding the organ clearances
The third is the sum of the organ clearances. The organs remove drug at the same time and independently, so their clearances add. The total clearance of the body equals the renal clearance plus the hepatic clearance plus the clearance by any other route. Urine collected over an interval gives the renal clearance: the amount of unchanged drug in this urine divided by the AUC over that interval. Nonrenal clearance is the total clearance minus the renal clearance.
4:32Ciprofloxacin
Ciprofloxacin, an antibiotic, shows how clearances add and how kidney function changes them. The kidneys excrete part of the dose unchanged, and metabolism and other nonrenal routes eliminate the rest. In healthy subjects given intravenous ciprofloxacin, the total clearance was 52.2 liters per hour. The renal clearance was 26.5 liters per hour, and the nonrenal clearance was 25.8, which add to about the total. About half of the dose appeared unchanged in urine. The calculated AUC for a 400 milligram intravenous dose in these subjects is 400 divided by 52.2, about 7.7 milligram hours per liter. For most drugs, dosing decisions depend on the AUC, and the dose that gives a target AUC equals the clearance times that AUC.
5:44Kidney function and clearance
Reduced kidney function lowers mainly the renal clearance. Its effect on the total clearance therefore depends on the size of the renal part. Creatinine is a waste product of muscle, and its clearance is a measure of kidney function. In patients with reduced kidney function, the renal clearance of ciprofloxacin was lower when the creatinine clearance was lower. The nonrenal clearance showed no correlation with the creatinine clearance, and the total clearance showed a weaker correlation than the renal clearance. The authors used these results to propose intravenous doses for these patients.
6:33Summary
In summary, clearance is the volume of plasma from which the body removes all of the drug per unit of time. After an intravenous dose, it equals the dose divided by the AUC. Each organ removes drug only from the blood that flows through it, and the organ clearances add. For ciprofloxacin, renal clearance was about half of the total in healthy subjects. In patients, only the renal part was lower when kidney function was lower. With a lower clearance, a lower dose gives the same AUC. This concludes lesson 5.1 on clearance.
Sources
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- Barriere SL, Catlin DH, Orlando PL, et al. Alteration in the pharmacokinetic disposition of ciprofloxacin by simultaneous administration of azlocillin. Antimicrob Agents Chemother. 1990. PMID 2360821
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Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.
