L-Carnitine ester of prednisolone: pharmacokinetic and pharmacodynamic evaluation of a type I prodrug.

PURPOSE

To evaluate whether PDSC, an L-carnitine ester derivative of prednisolone and OCTN2 substrate, could provide a targeted delivery of the corticosteroid into the lung tissues of an asthmatic guinea pig model.

METHODS

PRED (prednisolone) and PDC (an L-carnitine prodrug of prednisolone not recognized by OCTN2) served as controls. Water solubility and logP values were determined, and PDSC and PDC in vivo were quantified by LC-MS/MS.

RESULTS

Unlike PRED, the intra-tracheal instillation of PDSC resulted in effective and prolonged accumulation of prednisolone in the lung tissues, leading to 3.8-fold higher reduction in inflammatory cell count in the bronchoalveolar fluid, and less severe lung and bronchial lesions in the asthmatic guinea pig. PDC showed similar pharmacokinetic profile to PRED, but exhibited higher efficiency (1.7-fold higher) at reducing the inflammatory cell count and the severity of lung histopathology, possibly due to the release of L-carnitine in vivo.

CONCLUSIONS

The collective data suggest that PDSC has the potential to be an effective prodrug for the treatment of asthma with concomitant reduction in systemic side effects, and that novel prodrugs produced by L-carnitine conjugation can have useful applications in the targeted accumulation of drugs in the lungs.