![]() In addition to ethnic differences between the subjects investigated in the previous studies and Japanese subjects, the normally used daily doses of HMG-CoA reductase inhibitors differ from those in European and US populations (10 mg vs 40 mg, respectively). However, no studies have been conducted in Japanese subjects to date. Plasma concentrations of simvastatin, lovastatin, and atorvastatin, which are all metabolized by CYP3A4, are significantly increased when these drugs are taken with GFJ, whereas those of pravastatin are not affected by GFJ intake. The effects of GFJ intake on the pharmacokinetic disposition of simvastatin, lovastatin, atorvastatin, and pravastatin have already been examined. Thus in this respect, pravastatin is considered safer than the other HMG-CoA reductase inhibitors. However, since pravastatin is not metabolized by CYP3A4, there is a low possibility that it enters into such drug–drug interactions. Most of the HMG-CoA reductase inhibitors are metabolized by CYP3A4, and they may possibly interact with other drugs that act at CYP3A4 when taken concomitantly. HMG-CoA reductase inhibitors reduce blood cholesterol concentrations by competitive inhibition of HMG-CoA reductase, a rate-limiting factor in cholesterol biosynthesis. To decrease concentrations of cholesterol in the blood, three strategies have been considered: suppression of its absorption inhibition of its biosynthesis and promotion of its excretion. Hypercholesterolaemia is a major risk factor for ischaemic heart disease. Hence since GFJ is a commonly used beverage, it is of interest to investigate interactions between GFJ and various prescription drugs that are likely to be affected. In addition, GFJ inhibits P-glycoprotein efflux transporters located in the GI tract mucosa, thus enhancing uptake of P-glycoprotein substrate drugs from the intestinal tract. ![]() Concomitant use of GFJ is known to increase plasma concentrations of some dihydropyridine calcium antagonists, anti-allergic agents, immunosuppressive agents, and anti-HIV agents. Grapefruit juice (GFJ) contains various furanocoumarin derivatives that inhibit CYP3A4 located in the GI tract walls. During this process, some drugs are metabolized to some extent by enzymes such as cytochrome P-450 (CYP) complex enzymes in the liver, and by CYP3A4 in particular in the epithelial cells of the small intestine. Following oral administration, drugs are normally absorbed through the GI tract into the portal veins, and enter into the circulating bloodstream after passing through the liver. Yet along with the possibility of better therapeutic effects provided by combination drugs, problems caused by drug–drug interactions often arise. Multidrug therapy is common in the clinical setting.
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