Ethyl docosahexaenoate decreased Neoral ® absorption due to particle size enlargement

Abstract

We recently reported that docosahexaenoic acid (DHA) enhanced the bioavailability of cyclosporine A (CsA) in a conventional oil formulation by inhibiting CYP3A-mediated gut metabolism. The aim of this study was to evaluate the effect of ethyl docosahexaenoate (DHA-EE), the commercially available form of DHA, on the absorption of CsA from its microemulsion formulation, Neoral ®, in rats. AUC ∞, AUC 0–10 h and C max of CsA decreased significantly when DHA-EE was co-administered, indicating that CsA absorption was diminished by DHA-EE. The results using a laser nanoparticle size analyzer exhibited approximately 60-fold shifting of the microemulsoin particle size from 0.042 μm to 2.46 μm, when 1 mg/ml DHA-EE was added to the microemulsion solution in vitro. Considering that the absorption of microemulsified drugs may decrease with increase in the particle size, the observed pharmacokinetics change of CsA may be caused by microemulsion enlargement, due to physicochemical interactions with DHA-EE. Possible interactions between DHA-EE and emulsified drugs might be of clinical importance.