Microdialysis assessment of microfibrous collagen containing a P-glycoprotein-mediated transport inhibitor, cyclosporine A, for local delivery of etoposide.

Abstract

This study was designed to assess a local drug delivery system of an anticancer agent, etoposide (VP-16), using microfibrous collagen as a drug carrier. For this objective, the microdialysis method was utilized to investigate the local pharmacokinetics of VP-16. Microfibrous collagen sheets (CS) containing 20 mg/kg of VP-16 with and without 40 mg/kg of cyclosporine A (CyA) were prepared and applied on the liver surface of rats. VP-16 concentrations in the liver extracellular fluid (ECF) were monitored by a microdialysis method. The local application of CS containing VP-16 resulted in a relatively long maintenance of drug concentrations in the liver ECF with very low concentrations in plasma. The inclusion of CyA in the CS resulted in 2-fold and 3-fold increases of the AUC and MRT values of VP-16 in the liver ECF, respectively. The liver ECF-to-plasma AUC ratios of VP-16 were 32-39 and 0.17 with local CS application and iv administration, respectively, indicating a remarkable advantage of the local drug delivery system. A pharmacokinetic interaction experiment suggested that the observed increase of the liver ECF concentrations of VP-16 with CyA resulted from inhibition of the biliary excretion of VP-16 by CyA. We found that the local delivery of the CS containing CyA on the liver surface is advantageous in terms of the extent and duration of liver ECF drug concentrations, when CyA was included in the CS. The effect of CyA was probably derived from the inhibition of P-glycoprotein-mediated biliary excretion of VP-16 by CyA. The usefulness of the microdialysis technique for the assessment of the local drug delivery system was also demonstrated.