Drug Clearance

Article Author:
Gaither Horde
Article Editor:
Vikas Gupta
Updated:
5/11/2020 12:15:20 PM
PubMed Link:
Drug Clearance

Definition/Introduction

Understanding the concept of drug clearance is essential when determining the dosing of medications.  When a medication is administered intravenously, the drug ends up either in the blood plasma or redistributes into the extravascular volume. The drug present in the plasma can be removed from the body primarily through the kidneys and liver. Drug clearance is defined as the volume of plasma cleared of a drug over a specified time period.[1] Thus, the units of measurement for drug clearance is in is volume/time. Another equation can calculate clearance. Clearance is equal to the rate at which a drug is removed from plasma(mg/min) divided by the concentration of that drug in the plasma (mg/mL). The total ability of the body to clear a drug from the plasma is renal clearance plus hepatic clearance plus clearance from all other tissues.  It is important to be aware of the fact that clearance does not tell us the amount of drug cleared. For example, let’s say drug X has a renal clearance of 20 mL/min and hepatic clearance of 5 mL/min. The total clearance of drug X would be 25 mL of plasma is cleared of drug X per minute. 

Issues of Concern

Elimination kinetics play an essential role in drug clearance. In first-order kinetics, a constant fraction of the drug is cleared per unit time because the mechanisms used for elimination are not saturated. Thus, drug clearance does not vary with changes in the plasma concentration of a drug when drug elimination occurs by first-order kinetics. The vast majority of drug elimination takes place by first-order kinetics. In zero-order kinetics, the same quantity of drug is eliminated per unit time because the mechanisms used for elimination are saturated.  In zero-order kinetics, drug clearance can vary due to changes in the plasma concentration of a drug.[2]

As you can see from previous examples, drug clearance plays an important role in determining drug concentration and thus dosing regimens. Steady-state plasma concentration is inversely related to the total body clearance of a drug. The dosing rate is calculated by multiplying total body clearance by a drug’s desired steady-state concentration, assuming the drug is fully bioavailable. For patients with cardiac insufficiency, kidney and liver disease, drug clearance can be severely affected.  The ability of serum proteins to bind to drugs also can play a role in clearance. A decrease in serum proteins may cause an increase in free drug concentration in the plasma, thus increasing its rate of elimination from the body.[3][4]

Clinical Significance

For patients with renal or hepatic disease, care is necessary to adjust dosages. In patients with severe liver disease, maintenance dosages should be reduced based on the percent of hepatic clearance of the drug.[5][6] Dosing in kidney disease tends to be complicated. Many drug companies provide dosage guidelines for each stage of renal disease. Dose reductions are often necessary for patients with renal disease.[7] The interaction of drugs with the kidney, type of kidney disease, and creatinine clearance need factor into dosing and therapy. Another factor that merits consideration is age because drug clearance decreases as patients get older.[8][9]


References

[1] Toutain PL,Bousquet-Mélou A, Plasma clearance. Journal of veterinary pharmacology and therapeutics. 2004 Dec     [PubMed PMID: 15601437]
[2] Wadhwa RR,Cascella M, Steady State Concentration 2020 Jan;     [PubMed PMID: 31985925]
[3] Jokanovic N,Tan EC,Sudhakaran S,Kirkpatrick CM,Dooley MJ,Ryan-Atwood TE,Bell JS, Pharmacist-led medication review in community settings: An overview of systematic reviews. Research in social     [PubMed PMID: 27665364]
[4] Levy G, Pharmacokinetics in renal disease. The American journal of medicine. 1977 Apr;     [PubMed PMID: 851113]
[5] Delcò F,Tchambaz L,Schlienger R,Drewe J,Krähenbühl S, Dose adjustment in patients with liver disease. Drug safety. 2005;     [PubMed PMID: 15924505]
[6] Morgan DJ,Smallwood RA, Clinical significance of pharmacokinetic models of hepatic elimination. Clinical pharmacokinetics. 1990 Jan     [PubMed PMID: 2178850]
[7] Lea-Henry TN,Carland JE,Stocker SL,Sevastos J,Roberts DM, Clinical Pharmacokinetics in Kidney Disease: Fundamental Principles. Clinical journal of the American Society of Nephrology : CJASN. 2018 Jul 6;     [PubMed PMID: 29934432]
[8] Toto RD, Conventional measurement of renal function utilizing serum creatinine, creatinine clearance, inulin and para-aminohippuric acid clearance. Current opinion in nephrology and hypertension. 1995 Nov;     [PubMed PMID: 8591059]
[9] Butler JM,Begg EJ, Free drug metabolic clearance in elderly people. Clinical pharmacokinetics. 2008;     [PubMed PMID: 18399712]