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Difficulty: MediumPharmacokinetic and Pharmacodynamic Principles

A 54-year-old man with a mechanical mitral valve replacement is maintained on a stable daily dose of warfarin. His international normalized ratio (INR) has been consistently in the therapeutic range of 2.52.5 to 3.53.5 for the past six months. He presents to the urgent care clinic with a 2-day history of purulent drainage from a leg wound and is prescribed a 7-day course of oral trimethoprim-sulfamethoxazole. Four days later, he comes to the emergency department reporting recurrent epistaxis and large ecchymoses on his trunk. Laboratory evaluation reveals an INR of 7.27.2. Which of the following is the most significant pharmacokinetic mechanism responsible for this patient's current laboratory findings?

  1. A
    Eradication of normal intestinal flora leading to reduced endogenous vitamin K synthesis
  2. B
    Displacement of the anticoagulant from its binding sites on plasma albumin
  3. Inhibition of the cytochrome P450-mediated metabolism of the more potent enantiomerAnswer
  4. D
    Inhibition of the renal tubular secretion of the unchanged anticoagulant
  5. E
    Down-regulation of the vitamin K epoxide reductase complex in the liver

Answer

Inhibition of the cytochrome P450-mediated metabolism of the more potent enantiomer
The correct mechanism is the inhibition of the cytochrome P450-mediated metabolism of the more potent enantiomer. Warfarin is a racemic mixture, and its S-enantiomer provides the majority of the anticoagulant effect. Because S-warfarin is exclusively metabolized by the hepatic enzyme CYP2C9, any drug that inhibits this enzyme will drastically reduce warfarin clearance. Trimethoprim-sulfamethoxazole is a potent CYP2C9 inhibitor. Its addition to the patient's regimen blocked the metabolism of S-warfarin, leading to drug accumulation, an exaggerated anticoagulant effect, and clinical bleeding.

Step-by-Step Solution

1
Analyze the patient's clinical presentation and timeline.
The patient developed a severely elevated INR and bleeding diathesis four days after starting trimethoprim-sulfamethoxazole while on a stable dose of warfarin.
Establishing the precise timeline confirms an acute drug-drug interaction rather than a gradual underlying disease process.
2
Identify the pharmacokinetic properties of the affected drug (warfarin).
Warfarin is administered as a racemic mixture. The S-enantiomer is roughly three to five times more potent than the R-enantiomer and is predominantly metabolized by hepatic CYP2C9.
Understanding the specific enzymatic pathway of the active drug component is necessary to predict and verify interaction mechanisms.
3
Determine the exact effect of trimethoprim-sulfamethoxazole on this pathway.
Trimethoprim-sulfamethoxazole potently inhibits the CYP2C9 enzyme, which leads to decreased clearance and subsequent toxic accumulation of S-warfarin.
Matching the offending drug's inhibitory properties with the metabolic pathway of the victim drug isolates the definitive pharmacokinetic mechanism.

Key Concept

Pharmacokinetic drug-drug interactions involving cytochrome P450 2C9 inhibition
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Topics

Pharmacokinetic and Pharmacodynamic Principles

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