Pharmacokinetic study of three different formulations of l ‐tetrahydropalmatine in brain tissues of rats

l ‐Tetrahydropalmatine ( l‐ THP), an active alkaloid compound isolated from Rhizoma Corydalis‐yanhusuo, has been reported to possess biological activity for treating cocaine use. To enhance both oral bioavailability and brain penetration, three formulations of l ‐THP suspension, mixture of l ‐THP–puerarin and self‐microemulsifying drug delivery systems (SMEDDS) were prepared. A sensitive and reliable ultra‐high‐performance liquid chromatography with tandem mass spectrometry method was developed and validated for the simultaneous determination of l ‐THP and its active metabolite l ‐isocorypalmine ( l ‐ICP) in rat brain. Diazepam was used as the internal standard. The chromatographic separation was achieved on a Bonshell ASB C 18 column at 30°C using acetonitrile–aqueous formic acid as mobile phase in gradient mode. The linearity was validated over the concentration ranges of 4.00–2,500 ng/ml for l ‐THP and 0.400–500 ng/ml for l ‐ICP. Full method validation was within the acceptance limits. The method was successfully used to determine the pharmacokinetics of two analytes following oral administration of these three formulations to rats. A significant difference was observed in the main pharmacokinetic parameters between SMEDDS and the suspension, and a 3.25‐ and 2.97‐fold increase in the relative bioavailability of l ‐THP and l ‐ICP, respectively, was observed with the SMEDDS compared with the suspension formulation. It was concluded that SMEDDS enhanced the absorption of l ‐THP and l ‐ICP and delayed their release in brain.