Lipophilic Prodrug Of Danshensu: Preparation,Characterization And Oral Bioavailability Evaluation

Danshensu(3-(3,4-dihydroxyphenyl)lactic acid,DSS),one of the main hydrophilic components of Radix Salvia miltiorrhiza(Danshen in China),which has been widely applied in clinical treatments.Its pharmacological activities have been comprehensively studied including inhibiting platelet aggregation,decreasing the blood viscosity,scavenging oxygen free radicals,protecting the endothelial cell from homocysteine-induced dysfunction,improving heart function effects,antiinflammatory and anti-tumor activities.However,the development of therapeutic DSS for clinical application still faces challenges because of its low oral bioavailability.It has been reported that DSS had a low oral bioavailability in rats and eliminated rapidly from the systemic circulation.In this study,two derivatives of DSS,Acetyl DSS(ADSS)and Palmitoyl Danshensu(PDSS),were synthesized.PDSS was selected as the most suitable prodrug after a series of in vitro physical and chemical evaluations.Though the solubility of PDSS in water was only 0.055 mg/mL,its solubility in FaSSIF and FeSSIF reached 4.68 and 9.08 mg/mL,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 of 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 respectively enhanced up to 9.8-fold and 2.2-fold compared to that of DSS.Cmax was 1.67 ± 0.11 μg/mLfor PDSS and 0.81 ± 0.06 μg/mL for DSS.Thus,these results demonstrated that PDSS had much higher oral bioavailability and longer circulation time than its parent drug.The human serum albumin(HSA)binding rate of DSS,PDSS were 37%~41%,56%~62%,respectively.Fluorescence spectroscopy revealed that DSS can enhance fluorescence intensity of HSA with the K of 55555 L/moL,and the fluorescence intensity of HSA would decreased by adding PDSS with the K of 101123 L/moL.Also,The CD spectra data showed there were slight changes of HSA in the presence of DSS and PDSS,with the intact main structure of protein.