Pharmacokinetics And Metabolism Of Quaternary Protoberberine Alkaloids Of Corydalis Yanhusuo

This paper includes five parts:The first part: summary of the related literatureDocuments about the present research situation in the structures of Quaternary protoberberine alkaloids, cardiovascular pharmacological activities of Quaternary protoberberine alkaloids in Corydalis yanhusuo, pharmacokinetics and metabolism of Quaternary protoberberine alkaloidsThe second part: pharmacokinetics of dehydrocorydalmine (DHC) in rats after oral administration either in an pure form or in effective fraction of Corydalis yanhusuo, EFYDehydrocorydaline was the most abundant quaternary proberberine alkaloid in EFY and with clear cardiovascular pharmacological activities. A fully validated LC-ESI-MS/MS method was developed and has been successfully applied to the pharmacokinetic study of DHC when given in the two different dosage forms of the EFY and pure compound afer oral administration in rat. The dose of DHC and EFY were 97.5 mg/kg and 483 mg/kg, respectively, and the content of DHC was 20.19 g/100 g EFY. The Cmax and AUC0-∞of DHC after being given in EFY form were about 3.1 and 1.9 fold higher than that when given as pure compound, respectively. The t1/2 of DHC was also changed with about 2.7 fold longer in the EFY form than that in the pure form. The Tmax of DHC was decreased to 0.31 fold shorter than that when given as pure compound. Such differences in pharmacokinetic parameters between the two dosage forms indicated that the relative bioavailability of DHC increased after administration in the EFY form comparing with in pure form. The reasons for such differences might be that there may be P-gp inhibitors and that other components co-existing in the EFY may compete with DHC for being transported by P-gp, metabolized by P450 and binding to plasma protein.The third part: excretion of DHC in bile and urine in ratsThe total amounts of DHC as unchanged form excreted in bile and urine were evaluated in rats after oral administration of DHC at a dose of 97.5 mg/kg. The mean accumulated amounts of DHC excreted in bile over 48 h was 60.04±24.66% of dose, and the mean accumulated amounts of DHC excreted in urine over 96 h was 0.17±0.13 % of dose. So DHC was mainly excreted in bile after oral administration of DHC. The mean accumulated amounts of DHC in bile in just 2 h was 12.2±7.38% of dose, indicating that DHC can be absorbed quickly following oral administration. There might be huge first pass effect in liver after oral administration and account for the trace plama concentration. The fourth part: metabolism of DHC in ratsThe metabolites of DHC in rat bile and plasma were screened using a QTRAPTM, with information-dependent acquisition (IDA) with multiple reaction monitoring (MRM) as the survery scan to trigger enhanced product ion scan (EPI).18 metabolites in bile and 9 metabolites in plasma were screened out using this approach in rats after oral administration of DHC. Structures of four therein were identified and structures of other metabolites were deduced from their Enhanced Product Ion (EPI) spectrum. Besides the metabolism pathway of demethylation followed by glucuronidation and sulfation, oxidation, dioxidation and dioxidation-dehydrogenation metabolic pathways were discovered for the first time in the Phase I biotransformation reactions in rats of quaternary proberberine alkaloids.The fifth part: studies on the structure and pharmacokinetics of the isomer of DHCThe structure of the isomer of DHC was deduced by the biosynthesis of quaternary proberberine alkaloids and HPLC-ESI-MSn as pseudodehydrocorydaline. A semi-quantitative LC-ESI-MS/MS method was developed for the pharmacokinetic study of the isomer of DHC when given in the EFY afer oral administration in rat at a dose of 483mg/kg. The isomer seemed to be absorbed slower and eliminated faster from body than DHC, but had much higher relative bioavailability than DHC.