Effect of grapefruit juice on Sandimmun Neoral® absorption among stable renal allograft recipients

Background. The oral formulation of cyclosporin A (CsA)—Sandimmun—has a highly variable absorption. The development of a CsA microemulsion— Sandimmun Neoral—resulted in increased bioavail- Introduction ability, and decreased variability of absorption. The first oral formulation (Sandimmun) interacted with Cyclosporin A (CsA) has had a great impact on renal numerous other drugs and grapefruit juice. Several of allograft survival by reducing the rate and severity of these interactions might be explained by decreased rejection episodes [1]. However, the absorption from pre-systemic metabolism by a cytochrome-enzyme the first commercially available oral formulation (e.g. CYP3A4) located in the enteral mucosa, and/or Sandimmun (Sand) (Sandoz, Basel, Switzerland) was via the P-glycoprotein-mediated decreased transport of markedly variable both interpatiently and intrapatiCsA back from enterocytes into the gut lumen. The ently [2], which was of particular concern as CsA has purpose of this pharmacokinetic study was to investi- a narrow therapeutic window between sufficient gate the interaction between Sandimmun Neoral and immunosuppression and, among other side-effects, grapefruit juice. nephrotoxicity. The absorption was among others Method. Eight stable renal transplant recipients were dependent on metabolism in the gut [3], numerous studied during two 8-h sessions in a randomized cross- drugs [4], and grapefruit juice (GFJ ) [5]. over design with 4 weeks interval. Following an over- In order to achieve a bioavailability as consistent as night fast the patients ingested their habitual morning possible, a new CsA microemulsion was developed: dose of Neoral either with water or with grapefruit Sandimmun Neoral (Neoral ) (Novartis, Basel, juice. During the 8-h study period 10 blood samples Switzerland ) [2]. The absorption of CsA from this were taken for determination of CsA concentration. microemulsion formulation might be either; (i) paracelThese results formed the basis for calculation of area lular (through tight junctions or temporary openings under curve (AUC ), and half-life (t D ). Maximum in the membrane created by shedding of enterocytes concentration (C max ) and time until C max (t max ) were within the intestinal tract), and/or (ii) transcellular obtained from the concentration–time profile. (with or without intracellular metabolism) [6 ]. Results. The median AUC increased by 38% Consequently, using Neoral compared to Sand the (12–194%) (P<0.05) following co-administration of influence of enteral mucosa metabolism may be Neoral with grapefruit juice. There were no significant by-passed. changes in C max ,t max , and t D. CsA is mainly metabolized through cytochrome Conclusion. Co-administration of Sandimmun Neoral P450 (CYP3A4), which is localized both in the liver with grapefruit juice resulted in an increased bioavail- [7] and in the small bowel enterocytes [8]. Furthermore ability of CsA, indicating unchanged pre-systemic the enterocyte CYP3A4 was shown to be inhibited by enterocyte first-pass metabolism as compared to GFJ [8]. In a study of intravenous CsA vs oral Sand Sandimmun. There was no impact of an oral grapefruit it was demonstrated that co-administration with juice load on systemic clearance of CsA. It seems GFJ increased the absorption while the systemic prudent to advise renal allograft recipients treated with clearance was unaffected, indicating that the effect of Sandimmun Neoral not to ingest their medication with GFJ was due to diminished enterocytes metabolism of grapefruit juice. CsA [9]. Furthermore, the CsA absorption is modulated