PROBLEM:
Many of the cholesterol-lowering medications, HMG-CoA reductase inhibitors, are metabolized by the enzyme CYP3A4. Components of grapefruit juice however, are also metabolized by this enzyme. As a result, dangerous levels of medication may accumulate in the blood when taken with grapefruit juice, causing adverse or even fatal effects.

SPECIFIC AIMS:
In Vitro Microsome Study:
(1) Compare the effect of known CYP3A4 inhibitor, itraconazole, on the metabolism of pravastatin and simvastatin in human and rat liver microsomes.
(2) Study the effect of other cholesterol lowering drugs, such as fenofibrate and niacin, on the metabolism of pravastatin and simvastatin.

In Vivo Pharmacokinetics Study:
(3) Evaluate the effect of grapefruit juice on the pharmacokinetics of statins..

HYPOTHESIS:
If the inhibition of the enzyme CYP3A4 has a severe effect on the metabolism of cholesterol-lowering drugs, then the reduction rate of the drug will decrease. As a result, large amounts of the drug will accumulate in the body. Since grapefruit juice is metabolized by CYP3A4, identifying the effect of drug interactions between grapefruit juice and statins may prevent adverse effects associated with grapefruit juice and medications.