Abstract

Apicidin, a potential oral chemotherapeutic agent, possesses potent anti-histone-deacetylase activity. After oral administration, the total bioavailability of apicidin is known to be low (14.2%–19.3%). In the present study, we evaluated the factors contributing to the low bioavailability of apicidin by means of quantitative determination of absorption fraction and first-pass metabolism after oral administration. Apicidin was given to rats by five different routes: into the femoral vein, duodenum, superior mesenteric artery, portal vein, and carotid artery. Especially, the fraction absorbed (F_X) and the fraction that is not metabolized in the gut wall (F_G) were separated by injection of apicidin via superior mesenteric artery, which enables bypassing the permeability barrier. The F_X was 45.9% ± 9.7%, the F_G was 70.9% ± 8.1% and the hepatic bioavailability (F_H) was 70.6% ± 12.3%, while the pulmonary first-pass metabolism was minimal (F_L = 102.8% ± 7.4%), indicating that intestinal absorption was the rate-determining step for oral absorption of apicidin. The low F_X was further examined in terms of passive diffusion and transporter-mediated efflux by in vitro immobilized artificial membrane (IAM) chromatographic assay and in situ single-pass perfusion method, respectively. Although the passive diffusion potential of apicidin was high (98.01%) by the IAM assay, the in situ permeability was significantly enhanced by the presence of the P-glycoprotein (P-gp) inhibitor elacrider. These data suggest that the low bioavailability of apicidin was mainly attributed to the P-gp efflux consistent with the limited F_X measured in vivo experiment.