A 52-year-old woman with a history of a deceased-donor renal transplant 3 years ago presents to the clinic with fever, productive cough, and shortness of breath. She is maintained on a stable immunosuppressive regimen of tacrolimus and mycophenolate mofetil. Her blood pressure is 128/78 mmHg and pulse is 88/min. Laboratory tests show a serum creatinine of 1.1 mg/dL, which is unchanged from her baseline over the past year. She is diagnosed with community-acquired pneumonia, and oral clarithromycin is added to her regimen. If the physician were to leave the tacrolimus dose unchanged, which of the following best describes the anticipated changes in the pharmacokinetic parameters of tacrolimus?
- Decreased hepatic clearance resulting in a prolonged half-life and elevated steady-state concentrationAnswer
- BInduction of hepatic cytochrome P450 enzymes resulting in a shortened half-life and reduced steady-state concentration
- CDecreased volume of distribution resulting in a shortened half-life and elevated peak plasma concentration
- DDecreased glomerular filtration rate resulting in a prolonged half-life and elevated steady-state concentration
- EDisplacement from plasma binding proteins resulting in an increased volume of distribution and unchanged total steady-state concentration
Answer
Decreased hepatic clearance resulting in a prolonged half-life and elevated steady-state concentration
Clarithromycin is a macrolide antibiotic known to potently inhibit the hepatic cytochrome P450 3A4 (CYP3A4) enzyme. Tacrolimus, an immunosuppressant with a narrow therapeutic index, is extensively metabolized by CYP3A4. When these drugs are co-administered, clarithromycin significantly decreases the hepatic clearance () of tacrolimus. According to fundamental pharmacokinetic principles, a drug's half-life () is inversely proportional to its clearance, as defined by the equation (). Therefore, a decrease in clearance prolongs the half-life. Furthermore, the steady-state concentration () is also inversely proportional to clearance (). If the maintenance dose remains unchanged while clearance is reduced, the drug will accumulate over time, leading to an elevated steady-state concentration and a drastically increased risk of severe toxicity.
Step-by-Step Solution
Key Concept
Pharmacokinetic drug-drug interactions involving CYP450 enzyme inhibition and their predictable effects on half-life and steady-state concentrations.