Researchers investigating the effects of heart failure on the pharmacokinetics of antidiabetic medications develop a cohort of experimental animals with anthracycline-induced heart failure. The experimental animals are then administered an oral dose of metformin, and serum levels are monitored over time. The test is repeated in control animals with normal heart function and the results are shown below: Which of the following best explains the change in serum metformin levels seen in the experimental animals?

Question

Researchers investigating the effects of heart failure on the pharmacokinetics of antidiabetic medications develop a cohort of experimental animals with anthracycline-induced heart failure.  The experimental animals are then administered an oral dose of metformin, and serum levels are monitored over time.  The test is repeated in control animals with normal heart function and the results are shown below:  Which of the following best explains the change in serum metformin levels seen in the experimental animals?

Quizplus · Accepted Answer

11ec160b_3c2d_5dbf_9249_8f3b5e745ebd_MD0001_00 Heart failure can cause changes in pharmacokinetic parameters that can alter drug effectiveness and lead to increased toxicity. Decreased cardiac output leads to tissue hypoperfusion, lowering the volume of distribution of many drugs and reducing perfusion of organs responsible for drug clearance (eg, liver, kidneys). This can result in higher serum drug levels and a prolonged elimination phase, which can be particularly important for drugs with a narrow therapeutic index (eg, digoxin, antiarrhythmics). In this example, serum metformin levels are seen to increase in animals with experimentally induced heart failure. Because metformin is renally cleared, this effect is most likely due to decreased renal blood flow as a result of reduced cardiac output. Because of the risk of lactic acidosis, metformin should be used with caution in patients with heart failure or impaired renal function from other causes. (Choices A and D) Heart failure frequently causes high central venous pressure and hepatic congestion. The resulting impairment in nutrient and oxygen delivery leads to hepatocellular damage and downregulation of CYP enzymes involved in drug metabolism. Reduced hepatic blood flow also results in decreased drug delivery to the liver, further impairing hepatic drug metabolism and clearance. However, metformin is not metabolized by the liver; it is excreted unchanged by the kidney. (Choice C) Decreased tissue perfusion in heart failure typically leads to a reduced volume of distribution of most drugs. Although the extracellular fluid accumulation that occurs in decompensated heart failure can potentially increase the volume of distribution of water-soluble drugs, this increased distribution volume would result in a decrease in serum drug levels. (Choice E) Increased central venous pressure in heart failure can lead to intestinal wall edema with increased intestinal wall thickness. This can result in delayed or decreased intestinal drug absorption. However, this effect would be expected to cause reduced serum drug concentrations and delayed peak levels. Educational objective: Heart failure leads to reduced liver and kidney perfusion, resulting in reduced drug clearance. Metformin is excreted unchanged by the kidney; therefore, patients with significant renal insufficiency due to heart failure or other causes (eg, chronic kidney disease) are at increased risk of toxicity (eg, lactic acidosis).

Researchers Investigating the Effects of Heart Failure on the Pharmacokinetics