Intestinal Absorption and Activation of Decitabine Amino Acid Ester Prodrugs Mediated by Peptide Transporter PEPT1 and Enterocyte Enzymes

Publication date: Available online 19 February 2018 Source:International Journal of Pharmaceutics Author(s): Wenhui Tao, Dongyang Zhao, Mengchi Sun, Ziyu Wang, Bin Lin, Yu Bao, Yingying Li, Zhonggui He, Yinghua Sun, Jin Sun Decitabine (DAC), a potent DNA methyltransferase (DNMT) inhibitor, has a limited oral bioavailability. Its 5′-amino acid ester prodrugs could improve its oral delivery but the specific absorption mechanism is not yet fully understood. The aim of this present study was to investigate the in vivo absorption and activation mechanism of these prodrugs using in situ intestinal perfusion and pharmacokinetics studies in rats. Although PEPT1 transporter is pH dependent, there appeared to be no proton cotransport in the perfusion experiment with a preferable transport at pH 7.4 rather than pH 6.5. This suggested that the transport was mostly dependent on the dissociated state of the prodrugs and the proton gradient might play only a limited role. In pH 7.4 HEPES buffer, an increase in Peff was observed for L-val-DAC, D-val-DAC, L-phe-DAC and L-trp-DAC (2.89-fold, 1.2-fold, 2.73-fold, and 1.90-fold, respectively), compared with the parent drug. When co-perfusing the prodrug with Glysar, a known substrate of PEPT1, the permeabilities of the prodrugs were significantly inhibited compared with the control. To further investigate the absorption of the prodrugs, L-val-DAC was selected and found to be concentration-dependent and saturable, suggesting a carri...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research