• Clinical Pharmacokinetics

  • Renal Clearance (CL_r)

    • The kidneys are the principal organs for the excretion of water-soluble drugs and their metabolites from the body.^5,6  

      • Renal clearance (CL_r) 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 (f_u) 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:

                • CL_filtration = f_{u *} 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.⁸

                • "Probenecid inhibits both of the Organic AnionTransporters (OAT) in the basolateral membrane of cells in the proximal tubule. This results in reduced clearance and increased plasma level of drugs normally secreted by this mechanism (e.g. penicillin)." Attribution: Figure slightly modified from reference 8. Probenecid: PharmWiki (last modified May 22, 2022) https://tmedweb.tulane.edu/pharmwiki/doku.php/probenecid

      • 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).

                • "Major drug transporters expressed in human renal proximal tubule cells. ADP, adenosine diphosphate; ATP, adenosine triphosphate; DC, dicarboxylate; OA, organic anion; OC and , organic cation." Attribution: This figure corresponds to figure 1 of reference 9. Yin J Wang J Renal drug transporters and their significance in drug-drug interactions. Acta Pharm Sin B. 2016 August 9;6(5): 363-373. https://www.sciencedirect.com/science/article/pii/S2211383516301526?via=ihub

              • Net renal clearance is the sum of processes described by the following equation:

                •  

  • Clearance of Unchanged Drug and Metabolites^10,11

    • 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 f_e, is a very important parameter.

          • f_e  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 f_e is significant) and any renally cleared active or toxic metabolites can be reduced.¹³

            • 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.^12,13

  • Factors Affecting Renal Clearance^14,15  

    • Physicochemical Properties: The drug's molecular size, polarity (water solubility), and pKa are fundamental determinants.

    • Plasma Protein Binding: As mentioned, only unbound drug is available for glomerular filtration.

      • The effect of protein binding is less pronounced for drugs that are efficiently cleared by active tubular secretion.

    • Urine pH: This is a major factor for the excretion of weak acids and weak bases due to its effect on tubular reabsorption.

      • Normal urine pH can range from 4.5 to 8.0. Drug ionization state of a drug may changes of function of pH.

        • 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.

    • Urine Flow Rate: A high urine flow rate (diuresis) decreases the transit time of fluid through the tubules and reduces the concentration gradient for passive reabsorption.

      • Elevated urine flow rates can increase the renal clearance of drugs that undergo significant passive reabsorption.¹⁶

    • Renal Blood Flow: This affects the rate of delivery of drugs to the glomeruli and tubular secretory sites and is particularly important for drugs that are highly cleared by active secretion.

      • There are autoregulation systems in place to manage changes in renal blood flow and glomerular filtration rates.¹⁷

    • Patient Factors: Age is a significant factor, as GFR and renal function naturally decline with age; at age 80, renal clearance is typically reduced to about half of what it was at age 30.

      • 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.¹²  

      • Genetic polymorphisms in renal drug transporters can also lead to inter-individual variability in renal clearance.¹⁸  

  • By comparing a drug's measured renal clearance to the patient's GFR (often estimated from serum creatinine as creatinine clearance), one can make powerful inferences about the underlying renal handling mechanisms.¹⁹ 

    • The clearance by filtration is given by CL_filtration = f_u * GFR.

      • If the measured CL_r is about equal to this value, filtration is likely the dominant mechanism.

      • If CL_r is much greater then f_u * GFR, then it is highly suggestive of active tubular secretion is a significant contributor to elimination.

        • Alternatively, if CL_r is less than f_u * 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.²⁰

      • However, this view may be an oversimplification.

        • Some disease states may disproportionately affect tubular function while leaving GFR relatively preserved, or vice versa. 

          • For a drug that is primarily cleared by active secretion, dose adjustments based solely on a GFR estimate could be inaccurate and potentially dangerous.

          • 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.

          • First-Order Drug Elimination Kinetics

            Attribution: Graph 2 (contributed by Borowy C) from reference 22. Borowy C Ashurst J Physiology, Zero and First Order Kinetics. StatPearls. National Library of Medicine Bookshelf. (Last update: September 19, 2022).  https://www.ncbi.nlm.nih.gov/books/NBK499866/

             

      • Zero-Order (Non-Linear) Kinetics: Zero order kinetics occurs when the drug concentration is sufficiently high to saturate the elimination mechanisms.²³

        • 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

          • Zero-Order Drug Elimination Kinetics

            Attribution: Graph 1 (contributed by Borowy C) from reference 22. Borowy C Ashurst J Physiology, Zero and First Order Kinetics. StatPearls. National Library of Medicine Bookshelf. (Last update: September 19, 2022).  https://www.ncbi.nlm.nih.gov/books/NBK499866/

Updated June 2025

References