![]() |
![]() |
Clinical Pharmacokinetics
Renal Clearance
(CLr)
The
kidneys are the principal organs for the excretion of water-soluble
drugs and their metabolites from the body.
Renal clearance (CLr) is the component of total body clearance attributable to the kidney.
Renal clearance represents the net effect of three distinct processes that occur along the nephron, the functional unit of the kidney.
Mechanisms of Renal Excretion
Glomerular
Filtration:5
Glomerular filtration is a passive, non-saturable process that occurs at the glomerulus.
As blood flows through the glomerular capillaries, a portion of the plasma water and its dissolved solutes, including drugs, are filtered into Bowman's capsule to form the tubular fluid.
The rate of filtration is primarily dependent on the glomerular filtration rate (GFR), which is normally about 125 mL/min.
A key
constraint of this process is that only the unbound or free fraction (fu)
of the drug is filtered; drug molecules bound to large plasma proteins
like albumin are retained in the circulation.
Molecular
size is also a factor, with molecules larger than about 14 kDa generally
not being filtered.
The clearance by filtration can be expressed as:
CLfiltration = fu * GFR
Active
Tubular Secretion:6
Active tubular secretion is an active, energy-dependent transport process that occurs mainly in the proximal tubule.
This process involves carrier proteins that transport drugs from
the peritubular capillaries (blood) into the tubular fluid,
often against a concentration gradient.
Active tubular secretion is highly efficient and can clear even protein-bound drugs, as the high affinity of the transporters can bind free drug having Ddissociated from albumin.
There are separate, well-characterized transport systems
for organic anionic drugs (e.g., penicillins, diuretics,
probenecid) and organic cationic drugs (e.g.,
cimetidine, metformin, dofetilide).
Since tubular secretion depends on a finite number of
transporters, it is saturable and subject to competition
between drugs that share the same transport system.
This competition is the basis for certain therapeutic
drug interactions, such as the use of probenecid to
block the secretion of penicillin, thereby prolonging
its half-life.
![]() |
|
Tubular
Reabsorption:9
Tubular reabsorption is process by which drugs move from the tubular fluid back into the systemic circulation.
This process occurs primarily in the distal tubule and collecting duct.
For most
drugs, this is a passive process driven by the concentration gradient
that is created as water is reabsorbed from the tubule, concentrating
the drug in the remaining fluid.
This passive diffusion is highly dependent on the drug's:
Lipid solubility and
Ionization state.
Lipid-soluble, non-ionized drugs are readily reabsorbed across the
tubular membrane, whereas polar, ionized drugs are poorly reabsorbed and
are effectively "trapped" in the urine to be excreted.
Active
reabsorption mechanisms also exist for endogenous substances and some
drugs that resemble them (e.g., vitamins, glucose).
![]() |
|
Net renal clearance is the sum of processes described by the following equation:
![]() |
Clearance of Unchanged Drug and Metabolites10,11
The kidneys play a dual role in eliminating both the original parent drug and its metabolites.
Many
drugs, particularly those that are lipophilic, must first be
biotransformed in the liver into more polar, water-soluble metabolites
before they can be efficiently excreted by the kidneys.
These Phase I (e.g., oxidation via CYP enzymes) and Phase II (e.g., glucuronidation) reactions increase the water solubility of compounds, reducing their passive tubular reabsorption and facilitating their elimination in the urine.
Phase I reactions mediated by the cytochrome P450 drug metabolizing system alters the lipophilic drug by means of catalyzing oxidation, reduction, hydrolytic, and other reactions.10,11
Sometimes this transformation converts and inactive prodrug into the active form.
Oxidation is more likely to create metabolites with some pharmacological activity.
Phase I (as well as
phase II) reactions typically convert to lipophilic drug which can be
easily reabsorbed interval more polar compound more likely to be
excreted.10
Phase II reactions involve adding another molecule to the drug molecule (conjugation reaction).
The conjugate is typically water-soluble and pharmacologically inactive. Examples of conjugation mechanisms include glucuronidation, acetylation, sulfation and others.10,11
The
fraction of an administered dose that is excreted unchanged in the
urine, denoted as fe, is a very important
parameter.
fe quantifies the reliance of a drug's elimination on renal function.
The renal clearance can be calculated from the total clearance and this fraction:
![]() |
In
patients with renal impairment, the clearance of both the parent drug
(if fe is significant) and any renally cleared
active or toxic metabolites can be reduced.
Accumulation of such metabolites can lead to toxicity, even if the parent drug's concentration is within the therapeutic range.
Such
accumulation is an important consideration when treating patients with
kidney disease. pharmacotherapy for patients with kidney disease
Factors
Affecting Renal Clearance14,15
Physicochemical Properties: The drug's molecular size, polarity
(water solubility), and pKa are fundamental determinants.
The effect
of protein binding is less pronounced for drugs that are efficiently
cleared by active tubular secretion.
Normal
urine pH can range from 4.5 to 8.0.
For a weak acid (e.g., aspirin), alkalinizing the urine (increasing pH) increases the proportion of the ionized form, which is trapped in the tubule and excreted more rapidly.
Acidifying
the urine enhances the excretion of weak bases (e.g., amphetamine).
This
principle of "ion trapping" is used clinically in the management of
certain drug overdoses.
Elevated
urine flow rates can increase the renal clearance of drugs that undergo
significant passive reabsorption
Pathological conditions such as chronic kidney disease (CKD) and acute
kidney injury (AKI) may significantly decrease reduce renal clearance
and necessitate dosage adjustments for many drugs.
Genetic
polymorphisms in renal drug transporters can also lead to
inter-individual variability in renal clearance.
Alternatively, if CLr is less than fu
* GFR, it is probable that net tubular reabsorption is occurring,
returning some of the filtered drug back to the circulation.
This analytical approach provides insight into a drug's interaction with the kidney.
The common
clinical practice of adjusting drug doses in direct proportion to a
patient's decline in GFR is based on the "intact nephron hypothesis,"
which assumes that all aspects of renal function (filtration, secretion,
reabsorption) decline in parallel during disease.
Some
disease states may disproportionately affect tubular function while
leaving GFR relatively preserved, or vice versa.
This concern highlights an evolving area of clinical pharmacology focused on developing more sophisticated markers that can assess different renal pathways individually to allow for more precise dosage individualization.
Advanced Concepts in Drug Elimination and Accumulation
Capacity-Limited (Michaelis-Menten) Elimination
Most drugs, when administered at standard therapeutic doses, exhibit first-order elimination kinetics.
Some drugs, or any drug at a sufficiently high concentration, can overwhelm the body's elimination capacity, leading to a different and more complex kinetic profile.
First-Order versus Zero-Order Kinetics
First-Order (Linear) Kinetics: In this case the body's systems for elimination (e.g., metabolic enzymes, renal transporters) are not saturated.21,22
A constant
fraction of the drug is eliminated per unit of time.
The rate of elimination is therefore directly proportional to the plasma drug concentration.
For these drugs, clearance is a constant value, and the half-life is independent of the dose.
![]() |
|
Zero-Order (Non-Linear) Kinetics: Zero order kinetics occurs when
the drug concentration is sufficiently high to saturate the elimination
mechanisms.
Once
saturated, the system operates at its maximum capacity, and a constant
amount (e.g., milligrams per hour) of the drug is
eliminated per unit of time, irrespective of how high the plasma
concentration gets.
In this circumstance, clearance is not constant; it is variable and decreases as the drug concentration increases.
Also, the
half-life is not constant and becomes longer at higher concentrations.
Ethanol is a classic example of a substance that exhibits zero-order kinetics over most of its relevant concentration range
![]() |
|
Updated June 2025
![]() |
References
|