The Role of the Kidney in Drug Elimination
Recent advances in the identification and characterization of renal drug transporters and drug‐metabolizing enzymes has led to greater understanding of their roles in drug and chemical elimination and in modulation of the intrarenal exposure and response to drugs, nephrotoxic compounds, and physiological mediators. Furthermore, there is increasing awareness of the potential importance of drug–drug interactions (DDIs) arising from inhibition of renal transporters, and regulatory agencies now provide recommendations for the evaluation of transporter‐mediated DDIs. Apart from the well‐recognized effects of kidney disease on renal drug clearance, there is a growing body of evidence demonstrating that the nonrenal clearances of drugs eliminated by certain transporters and drug‐metabolizing enzymes are decreased in patients with chronic kidney disease (CKD). Based on these observations, renal impairment guidance documents of regulatory agencies recommend pharmacokinetic characterization of both renally cleared and nonrenally cleared drugs in CKD patients to inform possible dosage adjustment..
The kidney is responsible for the elimination of a myriad of drugs, nondrug xenobiotics, and endogenous compounds. Renal clearance is normally considered the net result of glomerular filtration, tubular secretion, and reabsorption, and characterization of the contribution of individual transporters expressed on basolateral and apical membranes of the tubule epithelium to drug and chemical excretion has advanced significantly over the last two decades. However, accumulating evidence additionally indicates that specific cytochromes P450 and UDP‐glucuronosyltransferases, and possibly other drug‐metabolizing enzymes, contribute to renal drug and chemical metabolic clearance, thereby modulating intrarenal exposure to these compounds as well as regulating the activity of physiological mediators. The impact of kidney disease on the clearance of drugs eliminated by filtration and secretion is well established, as is the requirement for drug dosage adjustment in patients with impaired renal function. Importantly, however, impaired renal function, including acute and chronic kidney disease and endstage renal disease, is additionally associated with decreased activity of several hepatic and gastrointestinal drug‐metabolizing enzymes and transporters. Here we highlight the roles of drug‐metabolizing enzymes and transporters in renal drug and chemical elimination and drug–drug interactions (DDIs), together with the scope of the effects of kidney disease on renal and nonrenal drug clearance and the extent to which impairment of enzyme and transporter activity is predictable.
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Relationship between Dosing Regimen and the Effect of a Drug
An individual’s response to a drug is determined by both the pharmacokinetics and pharmacodynamics of that drug. Pharmacodynamics is concerned with the effect of the drug on the body, including interactions between the drug, its target, and downstream biochemical effects. Pharmacokinetics describes the effect of the body on a drug and reflects the physiologic processes of absorption, distribution, metabolism, and excretion. Each of these processes may be altered in patients with kidney disease and affect therapeutic outcomes.
The concentration-time profile of a drug reflects the net effects of these pharmacokinetic processes after drug administration (Figure 1). The concentration-time profile approximates the clinical effect of most drugs, and drug exposure relates to the maximum plasma concentration (Cmax) and/or the area under the concentration-time curve (AUC). In general, high drug exposures increase the risk of adverse drug reactions, and low drug exposures are ineffective.
When the changes in pharmacokinetics due to kidney disease and other conditions are understood, the dosing regimen can be adjusted so that the concentration-time profile is optimized for the individual.
Reasons to Optimize Dosing Regimens
Either sub- or supratherapeutic dosing can occur when appropriate dose adjustments are not made in patients with kidney disease, and both have negative effects on patient outcomes, including morbidity, prolonged hospital admissions, and potentially, death. Subtherapeutic dosing increases the risk of treatment failure, which may be life threatening (e.g., anti-infectives) or organ threatening (e.g., immunosuppressive drugs). The risk of supratherapeutic exposure from drugs (or their active or toxic metabolites) that rely on kidney elimination is amplified when the drug has a narrow therapeutic index, such as digoxin or lithium. In many cases, accumulation develops over weeks, and the onset of drug toxicity is insidious. These principles are reflected in the examples below.
Summary
No matter what kind of medicine you take, whether OTC (over-the-counter) or prescription, it is destined to take a trip through your kidneys. Taking a drug the wrong way or in excessive amounts can damage these vital, bean-shaped organs and lead to serious complications. In the worst-case scenario, it could necessitate a kidney transplant.
“Compared with 30 years ago, patients today…have a higher incidence of diabetes and cardiovascular disease, take multiple medications, and are exposed to more diagnostic and therapeutic procedures with the potential to harm kidney function,” according to Cynthia A. Naughton, PharmD, senior associate dean and associate professor in the department of pharmacy practice at North Dakota State University. All of these factors are associated with an elevated risk of kidney damage.
An estimated 20% of cases of acute kidney failure are due to medications. The technical term for this scenario is “nephrotoxicity,” which is growing more common as the aging population grows, along with rates of various diseases.
The kidneys get rid of waste and extra fluid in the body by filtering the blood to produce urine. They also keep electrolyte levels balanced and make hormones that influence blood pressure, bone strength and the production of red blood cells. When something interferes with the kidneys, they can’t do their job, so these functions can slow down or stop altogether.
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