l‐Isocorypalmine, an active alkaloid compound isolated from Rhizoma Corydalis yanhusuo, has been reported to possess biological activity for treating cocaine use disorder. A high‐performance liquid chromatography coupled to Fourier transform ion cyclotron resonance mass spectrometry method was established for identification of the metabolites of l‐isocorypalmine in urine, plasma and feces samples of rats after a single intragastric gavage of l‐isocorypalmine at a dose of 15 mg/kg. As a result, a total of 21 metabolites (six phase І metabolites and fifteen phase II metabolites) were detected and tentatively identified by mass spectrometry and fragment ions from tandem mass spectrometry spectra. All metabolites were present in the urine samples, nine metabolites were found in the plasma samples and three metabolites were found in the feces samples. Results indicated that metabolic pathways of l‐isocorypalmine included oxidation, dehydrogenation, demethylation, sulfate conjugation, and glucuronide conjugation. In addition, glucuronidation was the major metabolic reaction. Results of this investigation could provide significant experimental basis for efficacy, safety and action mechanism of l‐isocorypalmine, which will be advantageous to new drug development for treating cocaine addiction.
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.
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