PHARMACOKINETIC STUDIES OF ADRIAMYCIN DELIVERED VIA MAGNETIC ALBUMIN MICROSPHERES AND OF IBUPROFEN IN SYNOVIAL FLUID (TARGET, PHYSIOLOGICAL, ANIMAL).

Abstract

Part I. Following a general historical review of the development of drug targeting, critical evaluations were made of current targeted drug delivery systems. Based on the results shown by previous studies, magnetic albumin microspheres containing adriamycin is one of the most promising targetable delivery systems for the treatment of solid tumors. It was also apparent that the pharmacokinetics of drugs associated with magnetic albumin microspheres had not been determined. A systematic study of the multiple variables involved in albumin microsphere preparation was completed to identify to what extent these variables affected the microsphere size distribution. The results of this investigation led to an optimal method of microsphere preparation. Information obtained from the above studies was applied to the production of magnetic albumin microspheres containing adriamycin suitable for in vivo use. The problems of separation and quantitation of adriamycin and adriamycinol in biological matrices were investigated using ion-pairing high pressure liquid chromatography. An optimized chromatographic system was presented for the analysis of these compounds in rat serum and tissues. The disposition of adriamycin following administration as magnetic albumin microspheres and as a solution was studied by monitoring adriamycin concentrations in multiple rat tissues for forty-eight hours after administration. The magnetic dosage form was targeted to a predefined tail segment with a magnetic field strength of 8000 G applied for 30 min after dosing. A physiological pharmacokinetic model was used to describe the disposition of adriamycin after both dosage forms. The model developed following adriamycin administration as a solution served as the foundation for the model for adriamycin when it was administered as the magnetic dosage form. Part II. The present investigation was designed to characterize the kinetics of ibuprofen in plasma and synovial fluid, which in the past, has been flawed by inadequate study protocols. After administration of a single dose and at steady-state, ibuprofen concentrations were measured simultaneously in plasma and synovial fluid obtained from eight patients with rheumatoid arthritis. The extent of accumulation of ibuprofen in each fluid was determined. The degree of ibuprofen protein binding in plasma and synovial fluid was also determined and related to its kinetic behavior.