Intestinal absorption and activation of decitabine amino acid ester prodrugs mediated by peptide transporter PEPT1 and enterocyte enzymes.

Autor: Tao W; Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China., Zhao D; Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China., Sun M; Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China., Wang Z; Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China., Lin B; Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China., Bao Y; Department of Pharmacology, Wuya College of Innovation, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China., Li Y; Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China., He Z; Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China., Sun Y; Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sunyinghua77@aliyun.com., Sun J; Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China. Electronic address: sunjin66@21cn.com.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2018 Apr 25; Vol. 541 (1-2), pp. 64-71. Date of Electronic Publication: 2018 Feb 19.
DOI: 10.1016/j.ijpharm.2018.02.033
Abstrakt: 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 P eff 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 carrier-mediated process (intrinsic K m : 7.80 ± 2.61 mM) along with passive transport. Determination of drug in intestinal homogenate after perfusion further confirmed that the metabolic activation mainly involved an intestinal first-pass effect. In a pharmacokinetic evaluation, the oral bioavailability of L-val-DAC, L-phe-DAC and L-trp-DAC were nearly 1.74-fold, 1.69-fold and 1.49-fold greater than that of DAC. The differences in membrane permeability and oral bioavailability might be due to the different stability in the intestinal lumen and the distinct PEPT1 affinity which is mainly caused by the stereochemistry, hydrophobicity and steric hindrance of the side chains. In summary, the detailed investigation of the absorption mechanism by in vivo intestinal perfusion and pharmacokinetic studies showed that the prodrugs of DAC exhibited excellent permeability and oral bioavailability, which might be attributed to a hybrid (partly PEPT1-mediated and partly passive) transport mode and a rapid activation process in enterocytes.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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