Determination of a novel potent immunosuppressant (FK-506) in rat serum and lymph by high-performance liquid chromatography with chemiluminescence detection

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FK-506 (I) a macrolide antibiotic extracted from the fermentation broth of Streptnmyces tmkuhaensis [ 11, has been shown to have strong immunosuppressive activity against a mixed lymphocyte reaction (MLR) [2]. In addition, intramuscular injection of I at 1 mg/kg per day will prolong graft survival in heterotropic cardiac allotransplantation in rats [3]. The pharmacological mechanism is considered to be a suppression of both interleukin 2 (IL-2) and IL-2 receptor expression on T cells [4]. The pharmacological activity of 1 is reported to be cu. 100 times greater than that of cyclosporin A (CyA) [5,6]. To perform a bioavailability study of I in both humans and dogs, an enzyme immunoassay (EIA) method has been established and used for the determination of plasma levels of I [7]. However, we cannot deny the existence of the crossreactivity of the antisera with some of the circulating metabolites of 1, as suggested from a pharmacokinetic study with CyA [8.9]. A biopharmaceutical study using EIA [8] showed that the amounts of I excreted into both the urine and the bile of dogs is less than 1% of the injected dose. Therefore, the main elimination pathway of I is thought to be the metabolism in the body. Thus, a new assay method specific to I in the plasma is needed to perform basic pharmacokinetic studies in experimental animals. In addition, we have been studying the relation-

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