Pharmacogenetic differences and drug–drug interactions in immunosuppressive therapy

Abstract

With the advent of new immunosuppressants and formulations, the elucidation of molecular targets and the evolution of therapeutic drug monitoring, the field of organ transplantation has witnessed significant reductions in acute rejection rates, prolonged graft survival and improved patient outcome. Nonetheless, challenges persist in the use of immunosuppressive medications. Marked interindividual variability remains in drug concentrations and drug response. As medications with narrow therapeutic indices, variations in immunosuppressant concentrations can result in acute toxicity or transplant rejection. Recent studies have begun to identify factors that contribute to this variability with the promise of tailoring immunosuppressive regimens to the individual patient. These advances have uncovered differences in genetic composition in drug-metabolising enzymes, drug transporters and drug targets. This review focuses on commonly used maintenance immunosuppressants (including cyclosporin, mycophenolate mofetil, tacrolimus, sirolimus, everolimus, azathioprine and corticosteroids), examines current studies on pharmacogenetic differences in drug-metabolising enzymes, drug transporters and drug targets and addresses common drug–drug interactions with immunosuppressant therapies. The potential role of drug-metabolising enzymes in contributing to these drug–drug interactions is briefly considered.

Keywords::

• CYP3A
• glucuronidation
• immunosuppressant
• MRP2
• P-glycoprotein
• pharmacogenetics
• transporters