Quantitative Determination of Absorption and First-Pass Metabolism of Apicidin, a Potent Histone Deacetylase Inhibitor

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% 6 9.7%, the F G was 70.9% 6 8.1% and the hepatic bioavailability (F H ) was 70.6% 6 12.3%, while the pulmonary firstpass metabolism was minimal (F L = 102.8% 6 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.

Mechanistic study of absorption and first‐pass metabolism of GL‐V9, a derivative of wogonin

“…According to AUC intraduodenal, por , only 50% of GL‐V9 was absorbed, which was related to intestinal peristalsis and solubility in the intestinal fluid. It is possible that the gastrointestinal absorption was saturated at a dose of 50 mg/kg (Shin et al, ). In a way, all these factors may increase the loss of GL‐V9.…”

“…Data are shown as the mean ± standard deviation (SD). The F a × F g , F gut wall , F h were calculated using following equations (Shin et al, ; Xiao et al, ): where AUC intraduodenal, sys , AUC iv , AUC mesentaryartery and AUC portal vein are the AUC 0‐10h of GL‐V9 in system blood after intraduodenal, intravenous, mesenteric artery and portal vein administration. AUC intraduodenal, por , Q por are AUC 0‐10h in the portal vein after intraduodenal administration and the portal blood flow, respectively.…”

Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors

“…Reductive metabolism to form thioether is also a common metabolic pathway of PPIs; however, the main organ and reductases of the reductive metabolism have not been reported (Fuhr and Jetter, 2002;Pu et al, 2018). By injection via the portal vein, drugs can enter into systemic circulation without undergoing first-pass metabolism in the intestine (Kunta et al, 2004;Shin et al, 2014). Rats were administered (R)-RAB via different routes, and the molar AUC 0-t ratios of thioether to RAB in the portal vein were significantly lower than those in systemic circulation after oral administration.…”

Preclinical formulation for the pharmacokinetics and efficacy of GBO-006, a selective polo like kinase 2 (PLK2) inhibitor for the treatment of triple negative breast cancer

“…GBO-006 showed very poor oral bioavailability (2-6 %) across mice, rats and dogs ( Figures 3, 4 and 6). Potential causes for the low oral bioavailability could be due to metabolism in the gut wall, and first-pass metabolism in the liver [17][18][19]. Following intravenous dosing to mice, rats and dogs, GBO-006 is rapidly eliminated from plasma within the first several hours with half-life estimates ranging from 0.5 to 0.7 h over this period.…”