Ethylene Glycol-Linked Amino Acid Diester Prodrugs of Oleanolic Acid for PepT1-Mediated Transport: Synthesis, Intestinal Permeability and Pharmacokinetics

• DOI: 10.1021/mp200447r
• Publication Date: 2012-02-21T23:46:00Z
• Authors: Feng Cao; Jinghao Jia; Zhi Yin; Yahan Gao; Lei Sha; Yisheng Lai; Qineng Ping; Yihua Zhang
• Keywords: Intestinal Permeability

The purposes of this study were to expand the structure parent drugs selected for peptide transporter 1 (PepT1)-targeted ester prodrug design and improve oral bioavailability oleanolic acid (OA), a Biopharmaceutics Classification System (BCS) class IV drug. Through an ethoxy linker carboxylic group OA was conjugated with different amino promoieties form six diester prodrugs. effective permeability (P(eff)) prodrugs screened by in situ rat single-pass intestinal perfusion (SPIP) model two buffers pH (6.0 7.4) as PepT1 employs proton-gradient driving force. Compared OA, 2.5-fold, 2.3-fold, 2.2-fold, 2.1-fold, 1.9-fold enhancement P(eff) buffer 6.0 observed L-Phe (5c), L-Val (5a), L-Lys (5e), D-Phe (5d), D-Val (5b), respectively. Furthermore, 5a, 5c, 5d 5e significantly higher than that 7.4 (p < 0.01), These results showed H(+) concentration solution had great effect on transport across membrane. For further evaluation affinity PepT1, inhibition studies performed coperfusing 0.1 mM 50 glycyl-sarcosine (Gly-Sar, typical substrate PepT1). It turned out 5b, 5c L-Tyr (6f) reduced presence Gly-Sar (1.7-fold, 1.9-fold, 1.4-fold, respectively). We supposed it may be attributed mediated these 5a 6f optimal target absorption vivo. Following intragastric administration 300 mg/kg (calculated OA) three groups rats, compared Cmax enhanced 1.56-fold 1.54-fold, Fapp 2.21- 2.04-fold increased, respectively, indicating better OA. combined also suggest which proper drug through can used PepT1-targeted design. With strategy, rats could improved significantly.