A lipophilic prodrug of Danshensu: preparation, characterization, and in vitro and in vivo evaluation

• Published in: Chinese journal of natural medicines 2017-05, Vol.15 (5), p.355-362
• Main Authors: GUO, Xue-Jiao, FAN, Xue-Jiao, QIAO, Bin, GE, Zhi-Qiang
• Format: Article
• Language: English
• Subjects: Animals; Biological Availability; Circulation time; Danshensu; Drug Compounding - methods; Drug Evaluation, Preclinical; Hydrogen-Ion Concentration; Lactates - chemistry; Lactates - pharmacokinetics; Male; Oral bioavailability; Prodrug; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Rats; Rats, Sprague-Dawley; Salvia miltiorrhiza - chemistry; Solubility
• ISSN: 1875-5364; 1875-5364
• DOI: 10.1016/S1875-5364(17)30056-0

Danshensu [3-(3, 4-dihydroxyphenyl) lactic acid, DSS], one of the significant cardioprotective components, is extracted from the root of Salvia miltiorrhiza. In the present study, an ester prodrug of Danshensu (DSS), palmitoyl Danshensu (PDSS), was synthesized with the aim to improve its oral bioavailability and prolong its half-life. The in vitro experiments were carried out to evaluate the physicochemical properties and stability of PDSS. Although the solubility of PDSS in water was only 0.055 mg·mL−1, its solubility in FaSSIF and FeSSIF reached 4.68 and 9.08 mg·mL−1, respectively. Octanol-water partition coefficient (log P) was increased from −2.48 of DSS to 1.90 of PDSS. PDSS was relatively stable in the aqueous solution in pH range from 5.6 to 7.4. Furthermore, the pharmacokinetics in rats was evaluated after oral administration of PDSS and DSS. AUC and t1/2 of PDSS were enhanced up to 9.8-fold and 2.2-fold, respectively, compared to that of DSS. Cmax was 1.67 ± 0.11 μg·mL−1 for PDSS and 0.81 ± 0.06 μg·mL−1 for DSS. Thus, these results demonstrated that PDSS had much higher oral bioavailability and longer circulation time than its parent drug.