Altered Pharmacokinetics in Disease (Renal/Hepatic Impairment)

Renal and hepatic impairment are the two organ failures that most predictably alter drug pharmacokinetics. Because the kidney and liver are the body's principal routes for eliminating drugs and their metabolites, a fall in renal or hepatic function reduces clearance, prolongs half-life, and can raise drug exposure - and impairment also changes drug distribution and metabolism through secondary effects on protein binding, fluid balance, and blood flow.

Definition

Altered pharmacokinetics in disease refers to the systematic changes in drug absorption, distribution, metabolism, and elimination produced by organ dysfunction - principally renal and hepatic impairment - that reduce clearance and modify drug exposure relative to people with normal organ function.

Scope

This topic covers how impaired kidney and liver function change the absorption, distribution, metabolism, and elimination of drugs: reduced renal clearance of drugs and active metabolites; reduced hepatic metabolism and altered first-pass extraction; and the indirect effects of organ disease on plasma protein binding, volume of distribution, and transporter and enzyme expression. It is a mechanistic reference topic and does not provide dosing rules.

Core questions

• How does reduced renal function change the clearance of renally eliminated drugs and metabolites?
• How does hepatic impairment alter drug metabolism and first-pass extraction?
• How do organ diseases change protein binding and distribution volume?
• Why is the effect of impairment greater for some drugs than others?

Key concepts

• Renal clearance and glomerular filtration
• Hepatic clearance and extraction ratio
• First-pass metabolism
• Active and toxic metabolite accumulation
• Plasma protein binding changes
• Volume of distribution shifts
• Half-life prolongation

Mechanisms

The kidney clears many drugs and water-soluble metabolites by glomerular filtration and tubular transport, so a reduced glomerular filtration rate lowers renal clearance and can allow active or toxic metabolites to accumulate (Hartmann et al., 2010). The liver clears drugs by metabolism and biliary excretion; hepatic impairment reduces metabolizing-enzyme capacity and, by lowering portal blood flow and disrupting the sinusoidal architecture, alters first-pass extraction so that the oral bioavailability of high-extraction drugs may rise (Verbeeck, 2008). Both diseases also change plasma protein concentrations and binding, shift fluid balance and volume of distribution, and can modulate the expression of metabolizing enzymes and transporters, so that exposure changes reflect a combination of reduced clearance and altered distribution (Wilkinson, 2005).

Clinical relevance

Renal and hepatic impairment are among the most common reasons drug exposure differs from the typical adult, making them central to evidence appraisal and to regulatory organ-impairment study requirements. This entry explains the disposition changes for reference and education; it describes mechanisms and is not a basis for dosing or individual treatment decisions.

Evidence & guidelines

Understanding here rests on clinical-pharmacology reviews of disposition in organ impairment. Regulatory authorities require and provide guidance for dedicated renal- and hepatic-impairment pharmacokinetic studies during drug development, which characterise how impairment shifts exposure for a given drug.

History

From the 1970s onward, clinical pharmacology established that organ failure systematically alters drug handling, with hepatic first-pass metabolism in liver disease and renal elimination in kidney failure documented as the leading mechanisms. This work underpins the modern expectation that drugs be characterised in renal and hepatic impairment.

Key figures

• Roger K. Verbeeck
• Frieder Keller
• Grant R. Wilkinson

Seminal works

• verbeeck-2008
• hartmann-2010
• wilkinson-2005

Frequently asked questions

Why does kidney or liver impairment raise drug exposure?

These organs are the main routes for eliminating drugs; when their function falls, clearance drops and half-life lengthens, so a given dose produces higher and more prolonged drug concentrations.

Does impairment affect every drug equally?

No. The effect is largest for drugs that depend heavily on the impaired organ for elimination, and smaller for drugs cleared mainly by the other organ or by routes the disease does not affect.