Clinical interaction between grapefruit juice and cyclosporine: is there any interest for the hematologists?

In the last few years a lot of reports dealt with pharmacokinetic interactions leading to elevated cyclosporine (CsA) blood concentrations. These interactions involve various drugs and food constituents, including antibiotics, antifungal agents, calcium antagonists, dietary lipids, and grapefruit juice.1,2 Grapefruit juice has been shown to significantly inhibit the gut wall cytochrome P 450 isoenzyme CYP 3A4, which is important in metabolism of CsA.3 The effect appears to be caused by the components of grapefruit juice, naringin, naringenin, or other flavonoids.4,5 The bioavailability of conventional CsA is low, with variable adsorption, clearance, and distribution; dosing, safe and effective use, and toxicity of the drug are still a matter of debate even though a better bioavailability has been observed with a new CsA microemulsion formulation.6 Recently, a study was presented7 on healthy adult volunteers, showing that coadministration of a defined dose of grapefruit juice could increase blood CsA concentration. A similar effect was observed in renal transplant recipients8 and also in patients with autoimmune rheumatologic diseases.9 However, it is still uncertain whether the effect of grapefruit juice may be sustained over time and whether it may contribute to maximize efficacy and minimize toxicity of CsA. So, we consider it useful to report on the satisfactory effect of grapefruit juice on blood CsA concentration and clinical outcome in four resistant, CsA-dependent, hematological patients followed for 9 months. Four patients (age 20 to 69 years) with hematological immune disorders were treated: a female with autoimmune hemolytic anemia (AIHA), a female with idiopathic throbocytopenic purpura (ITP), a male with AIHA in chronic lymphocytic leukemia (CLL), and a male with severe aplastic anemia (AA). With the exception of theAApatient, the other three patients were resistant to other immunosuppressive treatments and splenectomy, and the hematological remission was maintained with chronic administration of CsAfor 13 to 58 months. Further details on these patients have been reported elsewhere.10 The AApatient was on CsAwith water treatment for 3 months. Four patients (two AIHA women, one ITP woman, one AA man; age 28 to 62 years) having CsA only with water were followed for the same time as controls. After informed consent, the grapefruit juice (250 mL) was coadministered orally with cyclosporineAcapsules, outside the clinic. The drug daily dose (3 to 4 mg/kg to maintain the blood therapeutic values of 200 to 400 ng/mL) was administered simultaneously with the juice, half in the morning and half