Xiaoqiang Zhu,Weimin Kong,Zehua Wang,Xiaodong Liu,Li Liu
Background/Objectives:SPT-07A, a D-borneol, is currently being developed in China for the treatment of ischemic stroke. We aimed to create a whole-body physiologically-based pharmacokinetic (PBPK) model to predict the pharmacokinetics of SPT-07A in rats, dogs, and humans.Methods:The in vitro metabolism of SPT-07A was studied using hepatic, renal, and intestinal microsomes. The pharmacokinetics of SPT-07A in rats were simulated using the developed PBPK model and in vitro data. Following validation using pharmacokinetic data in rats, the developed PBPK model was scaled up to dogs and humans.Results:Data from hepatic microsomes revealed that SPT-07A was primarily metabolized by UDP-glucuronosyltransferase (UGTs). Glucuronidation of SPT-07A also occurred in the kidney and intestine. The in vitro to in vivo extrapolation analysis showed that hepatic clearance of SPT-07A in rats, dogs, and humans accounted for 62.2%, 87.3%, and 76.5% of the total clearance, respectively. The renal clearance of SPT-07A in rats, dogs, and humans accounted for 32.6%, 12.7%, and 23.1% of the total clearance, respectively. Almost all of the observed concentrations of SPT-07A following single or multi-dose to rats, dogs, and humans were within the 5th–95th percentiles of simulations from 100 virtual subjects. Sensitivity analysis showed that hepatic metabolic velocity, renal metabolic velocity, and hepatic blood flow remarkably affected the exposure to SPT-07A in humans. Dedrick plots were also used to predict the pharmacokinetics of SPT-07A in humans. Prediction accuracy using the PBPK model is superior to that of Dedrick plots.Conclusions:We elucidate UGT-mediated SPT-07A metabolism in the liver, kidney, and intestine of rats, dogs, and humans. The pharmacokinetics of SPT-07A were successfully simulated using the developed PBPK model.
Zhe Dong,Yu Zhao,Jinliang Chen,Ming Chang,Xiaosan Wang,Qingzhe Jin,Xingguo Wang
Borneol esters have attracted increasing interest due to their potential application in the food industry. In this study, the extraction of d -borneol from Cinnamomum camphora chvar. borneol seed was carried out via steam distillation to gain highly purified d -borneol (99.66%). The lipase-catalyzed lipophilization of extracted d -borneol with oleic acid was performed in a solvent-free system. The influences of lipase type, substrate molar ratio, lipase loading, reaction temperature and reaction time on d -bornyl oleate yield were evaluated. Among four kinds of commercial lipases screened for their esterification efficiency, CRL (lipase from Candida rugose ) displayed the highest catalytic activity in the synthesis of d -bornyl oleate. The yield of more than 95% was obtained under the optimal conditions: substrate molar ratio 1:2 ( d -borneol/oleic acid), lipase loading 8%, reaction temperature 45 °C, reaction time 48 h. The structural identification of d -borneol and product d -bornyl oleate was performed by gas chromatography mass spectrometry (GC-MS) and proton nuclear magnetic resonance spectroscopy ( 1 H NMR). The results showed that the product was confirmed to be d -bornyl oleate and the purity of which was 97.51%. This study will pave the way for d -borneol and its esters application in food industry.
危险品化学品经营许可证（带存储）