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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Efflux of Depsipeptide FK228 (FR901228, NSC-630176) Is Mediated by P-Glycoprotein and Multidrug Resistance-Associated Protein 1

Division of Pharmaceutics, College of Pharmacy (J.J.X., A.B.F., P.W.S., J.C., K.K.C.), Division of Hematology Oncology, College of Medicine and Public Health (J.B., G.M., K.K.C.), Department of Pharmacology, College of Medicine and Public Health (Y.H., Z.D., W.S.), and Division of Human Cancer Genetics (S.L., G.M.), The Ohio State University, Columbus, Ohio

Depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7[(Z)-ethylideno]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone], a novel histone deacetylase (HDAC) inhibitor, previously was reported to be a P-glycoprotein (Pgp) substrate. We now expand the investigation to demonstrate that FK228 is a substrate for Pgp and multidrug resistance-associated protein 1 (MRP1). Transport of FK228 across the Caco-2 cell monolayer in apical to basolateral (APBL) and basolateral to apical (BLAP) directions in the absence and presence of Pgp and MRP inhibitors were investigated. An in vitro uptake study in human red blood cells (RBCs) and a cytotoxicity assay in MRP1(-) HL60 and MRP1(+) HL60Adr cells were conducted to show that FK228 is an MRP1 substrate. An FK228-resistant cell line (HCT15R) was developed from HCT15 colon carcinoma and characterized using a 70-oligomer cDNA microarray, reverse transcription-polymerase chain reaction, Western blot analysis, histone acetyltransferase (HAT) and HDAC activity assays, and cytotoxicity assays. FK228 showed a nearly unidirectional flux across the Caco-2 cell monolayer, with the BLAP apparent permeability coefficient (P_app) 32 times that of APBL without apparent saturation. Pgp inhibition decreased the BLAP P_app and increased the APBL P_app. RBC showed a concentration-dependent uptake and saturable efflux of FK228. HL60Adr cells were 4-fold more resistant to FK228 than HL60 cells, and the resistance was reversed by MRP inhibition. Up-regulation of Pgp, but not changes of MRPs or HAT/HDAC enzymatic activities, was the major mechanism for the acquired FK228 resistance. These studies demonstrate that FK228 is a substrate for Pgp and MRP1, and reversible Pgp up-regulation is predominantly involved in FK228 resistance in vitro.

Address correspondence to: Dr. Kenneth K. Chan, Room 308 OSU CCC, The Ohio State University, 410 West 12th Avenue, Columbus, OH 43210. E-mail: chan.56{at}osu.edu

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