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

Abstract

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 C18 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.

A Comprehensive Review on the Chemical Properties, Plant Sources, Pharmacological Activities, Pharmacokinetic and Toxicological Characteristics of Tetrahydropalmatine

“…To improve absorption efficiency, the absorption level and rate of THP in a self-microemulsifying drug delivery system (SMEDDS) pellet formulation are higher than those of raw excipients( Tran et al, 2016 ). The SMEDDS improved the oral bioavailability of THP in a rabbit model by 198.63% ( Tung et al, 2018 ) and in a rat model by 225% ( Li et al, 2021 ) compared with THP suspension. The figures for self-emulsifying drug-delivery systems were 33.2% in a rat model ( Ma et al, 2012 ) and 234.77% for binary amorphous solid dispersion application in rabbit plasma ( Tung et al, 2021 ).…”

Self-Emulsifying Drug Delivery Systems: An Alternative Approach to Improve Brain Bioavailability of Poorly Water-Soluble Drugs through Intranasal Administration

“…A small number of SEDDS-based products have already been successfully introduced into the pharmaceutical market, with none of them loading drugs for the treatment of neurological disorders. Until now, several in vivo assays using oral SEDDS have been carried out for neuropharmaceuticals brain targeting [ 4 , 6 , 23 , 24 , 25 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 70 ], but only a few in vivo pre-clinical studies have been reported for IN administration of neurotherapeutics loaded in SEDDS. In fact, only six studies were found that investigated the IN administration of neurotherapeutics loaded in SEDDS: clonazepam [ 45 ], diazepam [ 44 ], and perampanel [ 28 ] for epilepsy treatment; Bdph for glioblastoma treatment [ 4 ]; huperzine A [ 30 ] for Alzheimer’s disease; and naringin [ 5 ] as a neuroprotective for Alzheimer’s and Parkinson’s disease.…”