The term "clearance percentage" is often used colloquially but is not a formal pharmacokinetic term. In pharmacology, clearance ($CL$) is defined as the volume of plasma from which a substance is completely removed per unit of time, typically expressed in mL/min or L/hr. However, the efficiency or rate of elimination can be quantified as a percentage of the total drug presented to an organ or using comparative ratios. This article explains how to properly assess this drug removal efficiency, focusing on the critical roles of the kidneys and liver.
Total Body Clearance and the AUC Method
Total body clearance ($CL_T$) represents the sum of all individual organ clearances, primarily the liver ($CL_H$) and kidneys ($CL_R$) for most drugs. Pharmacokinetic studies can determine total clearance using the Area Under the Curve (AUC), which measures a drug's total systemic exposure over time.
The most common formula for total clearance is:
- For intravenous (IV) administration, where bioavailability (F) is 1: $CL_T = \frac{Dose}{AUC}$.
- For extravascular (e.g., oral) administration: $CL_T = \frac{F \times Dose}{AUC}$.
While AUC measurements are standard in clinical trials, they are not practical for routine clinical practice. Therefore, other methods are used to estimate organ-specific clearance and assess its efficiency.
Estimating Renal Clearance
For many drugs, renal excretion is the primary clearance pathway. Clinicians estimate renal function and a drug's renal clearance ($CL_R$) by using endogenous markers like creatinine.
The Role of Creatinine Clearance
Creatinine is a waste product from muscle metabolism that is consistently produced and primarily excreted by the kidneys. Creatinine clearance ($CrCl$) is used to estimate the glomerular filtration rate (GFR), which measures how well the kidneys are filtering waste from the blood.
One of the most widely used formulas to estimate CrCl is the Cockcroft-Gault equation:
$CrCl = \frac{(140 - age) \times weight}{72 \times SCr} \times 0.85$ (for females)
Where age is in years, weight is in kg, and SCr (serum creatinine) is in mg/dL. The result is an estimate of the volume of plasma cleared per minute (mL/min), providing a critical assessment of renal function.
The Renal Clearance Ratio
A more direct way to understand the "percentage" of drug handled by the kidneys is through the renal clearance ratio. This ratio compares a drug's clearance to that of inulin, a substance that is only filtered by the glomerulus and is not secreted or reabsorbed.
$Clearance \ Ratio = \frac{CL{drug}}{CL{inulin}}$
- Ratio > 1: The drug is actively secreted by the renal tubules, indicating high renal clearance efficiency.
- Ratio = 1: The drug is handled like inulin (filtered only).
- Ratio < 1: The drug is either bound to plasma proteins or actively reabsorbed back into the bloodstream.
Estimating Hepatic Clearance
For drugs primarily eliminated by the liver, assessing hepatic clearance ($CL_H$) is key. The most relevant "percentage" concept here is the hepatic extraction ratio ($E_H$).
The Hepatic Extraction Ratio
$E_H$ is the fraction of drug entering the liver that is removed in a single pass. It is a value between 0 and 1 (or 0% to 100%) and is determined by comparing the drug concentration in blood entering the liver (arterial) with that leaving the liver (venous).
$EH = \frac{Concentration{in} - Concentration{out}}{Concentration{in}}$
Based on this ratio, drugs are classified into categories with different implications for clearance:
- High Extraction Ratio (>0.7): Clearance is highly dependent on hepatic blood flow. The liver is very efficient at removing the drug.
- Low Extraction Ratio (<0.3): Clearance is more dependent on the liver's intrinsic metabolic capacity and the fraction of unbound drug. The liver is inefficient at clearing the drug in a single pass.
Comparison of Renal vs. Hepatic Clearance Parameters
| Parameter | Renal Clearance ($CL_R$) | Hepatic Clearance ($CL_H$) |
|---|---|---|
| Primary Metric | Creatinine Clearance (CrCl) or Renal Clearance Ratio | Hepatic Extraction Ratio ($E_H$) |
| Dependent Factors | GFR, Active secretion/reabsorption, Urine pH, Protein binding | Hepatic blood flow, Intrinsic metabolic clearance, Fraction unbound drug |
| Efficiency Indicator | Clearance ratio relative to inulin helps determine renal handling mechanism | Extraction ratio classifies drugs as high, low, or intermediate extraction |
| Calculation Method | Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD) formula, or lab measurement | Based on liver blood flow, extraction ratio, and unbound fraction |
| Clinical Application | Dose adjustment for renal impairment | Dose adjustment for hepatic impairment or blood flow changes |
The Clinical Importance of Checking Clearance
Assessing clearance, and thus the efficiency of drug elimination, is crucial for patient safety and therapeutic effectiveness. Incorrect dosing due to unmonitored changes in clearance can lead to drug accumulation and toxicity or, conversely, sub-therapeutic drug levels. For example, patients with impaired kidney function require a dose reduction of renally cleared drugs to avoid accumulation. Similarly, a drug's high hepatic extraction ratio means its clearance is sensitive to changes in liver blood flow, which can occur during heart failure or with co-administered medications.
To check clearance efficiency, a clinician may:
- Order a serum creatinine test to estimate renal function via CrCl or GFR formulas.
- Review liver function tests, although these are less directly correlated with hepatic clearance, the clinical context is important.
- Adjust doses based on a patient's renal or hepatic status, as indicated by standard dosing guidelines or a pharmacist's recommendations.
In essence, while you won't find a single "clearance percentage" value, understanding the concepts of extraction ratio and clearance ratios for different organs allows for a nuanced and medically accurate assessment of drug elimination efficiency.
Conclusion
Clearance is a dynamic and essential pharmacokinetic parameter that measures the efficiency of drug elimination from the body. While the term "clearance percentage" isn't technically accurate, the underlying concept is crucial for safe and effective medication use. By analyzing total clearance via methods like the AUC, or assessing organ-specific clearance using metrics such as the creatinine clearance or hepatic extraction ratio, clinicians can appropriately adjust medication doses for patients with varying organ functions. Ultimately, a deep understanding of drug clearance mechanisms is fundamental to the practice of clinical pharmacology and therapeutic drug monitoring. The National Kidney Foundation provides helpful information on kidney-related clearance estimation.
