Drug Interactions Newsletter

Volume 1, Issue 22, 06/16/2009

Question

What is the mechanism by which the immunosuppressant, cyclosporine (Gengraf®, Sandimmune®, Neoral®) increases the cholesterol absorption inhibitor, ezetimibe (Zetia®), blood concentrations over 3-fold?

Answer

It is well known that developments in immunosuppressive therapy during the past two decades have led to the improvements in organ rejection related mortality.(1)  However, a significant number of transplant patients will develop post-transplantation hyperlipidemia which is caused in part by many of the immunosuppressant medications.(2-4)  Commonly prescribed immunosuppressants include azathioprine (Imuran®), cyclosporine (Gengraf®, Sandimmune®, Neoral®), mycophenolate (CellCept®), sirolimus (Rapamune®), and tacrolimus (Prograf®).  A closer inspection of cyclosporine reveals that in addition to increasing the risk for post-transplantation cardiovascular complications that will require lipid lowering therapy, it also causes many drug-drug interactions.(4-9)  One such interaction is with the cholesterol absorption inhibitor, ezetimibe (Zetia®).(6-10)  This interaction results in a greater than 3-fold increase in ezetimibe blood concentrations.  Interestingly, ezetimibe does not undergo any appreciable metabolism via the cytochrome P450 (CYP) enzyme system but rather is metabolized primarily through UDP-glucuronosyltransferase (UGT) enzymes which cyclosporine does not significantly inhibit.  If not through enzyme inhibition, then by what mechanism does cyclosporine cause this increase in ezetimibe concentrations? 

After oral administration, ezetimibe passes into the small intestine where it enters into the enterocyte where it predominately undergoes....

There is a figure available with this newsletter that helps to explain this drug interaction.

Other keywords found in this issue:  glucuronidation, transporters, enterocyte, hepatocyte, enterohepatic recycling,

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