The ABCs of ADME in AKI

The pharmacokinetics of a drug refers to the study of the absorption, distribution, metabolism and elimination of that drug (often referred to as ADME). Each of these characteristics can be greatly altered in a patient presenting with acute kidney injury (AKI). Historically, dosing in AKI has not been distinguished from that of chronic renal insufficiency (CRI). Newer evidence suggests that pharmacokinetic alterations differ between AKI and CRI, and; therefore, dose adjustments may also be different.

Absorption

The bioavailability of a drug can be influenced by GI transit time, gastric pH, and intestinal drug metabolism. Gastric pH can be increased in patients presenting with AKI, which may decrease dissolution and ionization of the oral drug and lead to reduced absorption. In CRI, intestinal metabolism can be reduced potentially resulting in increased absorption. The effect of AKI on intestinal metabolism has not been well-studied.

Distribution

Drug distribution is dictated by many factors, one of which is a medication’s ability to bind to plasma proteins, such as albumin. Patients with AKI may present with low serum albumin levels, leading to a higher free-fraction of albumin-bound drugs (e.g. warfarin, phenytoin, valproic acid, and salicylates) and consequently, increased biological effect.

Other factors affecting drug distribution include serum pH and fluid status. AKI is frequently associated with acidosis, which may affect the ionization and ultimately the distribution of the drug into the tissues. Lastly, increase in fluid volume in the blood can lead to low drug concentrations.

Metabolism

Many drugs undergo metabolism prior to elimination. A myriad of co-morbid conditions frequently associated with AKI may affect drug metabolism such as liver and cardiac dysfunction. Non-renal clearance can be decreased in the setting of CRI, possibly due to a chronic accumulation of uremic by-products causing an impairment of drug metabolic enzymes. As this is a chronic process, the same may not hold true in the early stages of AKI.

Elimination

AKI may have opposite effects on drug elimination. While significant nephrotic syndrome may increase the clearence rate of large molecules and highly protein-bound drugs, acids and bases may accumulate in AKI and compete for transporters, thus diminishing tubular secretion of drugs eliminated by anionic and cationic transport systems.

In sum, the pathophysiologic process in AKI is different from that of chronic CRI, and the pharmacokinetic parameters of medications may differ in the two disease states. Therefore, drug dosing principles studies in CRI may not hold true for patients presenting with AKI, and further research will be necessary to ensure proper dosing of medications in AKI and better guide us in our daily clinical decisions.

Craig A. Stevens PharmD, PGY1 Pharmacy Practice Resident

Steven Gabardi PharmD, BCPS, Organ Transplant Clinical Specialist at BWH

References

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Power BM, Forbes AM, van Heerden PV, Ilett KF. Pharmacokinetics of drugs used in critically ill adults. Clin Pharmacokinet 1998;34:25-56.