A 34-year-old kidney transplant patient treated with cyclosporine comes to the office due to nausea and anorexia. The patient underwent transplantation 6 months ago and had been doing well until recently. On examination, his blood pressure is 160/96 mm Hg. There is no tenderness at the site of the transplanted kidney. Serum creatinine is 3.4 mg/dL, and the serum cyclosporine level is markedly increased. A month ago, he had normal blood pressure and normal levels of cyclosporine and serum creatinine. Further questioning reveals that the patient has been drinking increased amounts of grapefruit juice lately as part of an attempt to improve his overall health. Which of the following mechanisms is most likely responsible for this patient's current condition?

Question

A 34-year-old kidney transplant patient treated with cyclosporine comes to the office due to nausea and anorexia.  The patient underwent transplantation 6 months ago and had been doing well until recently.  On examination, his blood pressure is 160/96 mm Hg.  There is no tenderness at the site of the transplanted kidney.  Serum creatinine is 3.4 mg/dL, and the serum cyclosporine level is markedly increased.  A month ago, he had normal blood pressure and normal levels of cyclosporine and serum creatinine.  Further questioning reveals that the patient has been drinking increased amounts of grapefruit juice lately as part of an attempt to improve his overall health.  Which of the following mechanisms is most likely responsible for this patient's current condition?

Quizplus · Accepted Answer

This patient's new-onset hypertension and elevated levels of serum creatinine and cyclosporine are suggestive of acute calcineurin inhibitor nephrotoxicity. Calcineurin inhibitors such as cyclosporine cause dose-dependent renal vasoconstriction and tubular cell damage, which can precipitate acute renal failure. Cyclosporine is extensively metabolized by the liver and gastrointestinal tract via the cytochrome P450 system, specifically the CYP3A isoenzymes. Inhibition of intestinal P450 enzymes by the furocoumarins present in grapefruit juice can slow the breakdown of drugs metabolized by this pathway, raising circulating levels of the affected drugs. Medications with a narrow therapeutic index (eg, cyclosporine) have the highest risk of toxicity. (Choice A) Changes in gastric pH do not significantly affect the oral bioavailability of cyclosporine. (Choice C) Transmembrane cyclosporine transport is not affected by grapefruit juice. (Choice D) Pharmacodynamic potentiation is defined as a greater than additive effect that occurs when 2 different drugs are administered simultaneously due to functional interactions within the target tissues. Grapefruit juice increases the effect of cyclosporine by slowing its metabolism, which is a pharmacokinetic mechanism. (Choice E) A decrease in plasma protein binding could lower the apparent volume of distribution of a fixed dose of cyclosporine, thereby increasing the amount of free drug in circulation. However, grapefruit juice does not influence the binding of cyclosporine to plasma proteins. Educational objective: Calcineurin inhibitor nephrotoxicity with resultant impairment of renal function is the most significant adverse effect of cyclosporine. Cytochrome P450 3A (CYP3A) is responsible for cyclosporine metabolism in the small intestine and liver. Grapefruit juice inhibits this enzyme and increases the nephrotoxicity of cyclosporine by raising circulating drug levels (pharmacokinetic interaction). __________ References: The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. (http://www.ncbi.nlm.nih.gov/pubmed/7697949)

A 34-Year-Old Kidney Transplant Patient Treated with Cyclosporine Comes to the Office