AIM: To provide primarily pharmacokinetic profiles and reveal potentially pharmacological components after oral administration of the extractum for Compund Danshen Dripping Pill (CDDP) in rats, which was mainly compos...AIM: To provide primarily pharmacokinetic profiles and reveal potentially pharmacological components after oral administration of the extractum for Compund Danshen Dripping Pill (CDDP) in rats, which was mainly composed of protocatechuic aldehyde (PAL), Danshensu (DSS), lithospermic acid A, lithospermic acid B, salvianolic acid D, rosmarinic acid, salvianolic acid B and salvianolic acid A. METHODS: After orally administration of 200 mg CDDP extractum for 1 h, the portal vein blood, the femoral artery blood, the bile and urine samples were separately collected. The gastrointestinal (GI) contents and mucosa were washed with physiological saline and the washing solution was pooled. The whole GI tract was removed and homogenized for analysis. The constituents and concentrations of all above samples were determined by the LC-MS analysis combined with the β-glucuronidase and sulfatase treatment. RESULTS: The investigation after oral administration of CDDP extractum for 1 h in rats indicated that: (1)Most of polyphenolic acids have been degraded into caffeic acid (CA) and DSS in the GI tract. Next, CA could be easily absorbed into blood circulation and a trace of DSS was also transported into the portal vein. The remains of undegraded polyphenolic acids and Danshensu were detained in the GI tract lumen. (2)Part of PAL was firstly oxidized into PAC in GI epithelial cells before absorption into the portal vein. Next, PAC and the rest PAL were further transported into blood circulation. (3)PAC and PAL were distributed in blood circulation in free and conjugated forms after being glucuronidated in the liver and the kidney while only free CA and DSS appeared in vivo. After that, all of these metabolites were gradually secreted into bile and urine. CONCLUSION: The results suggest that DSS, PAL, PAC, CA and their conjugated forms may be potential pharmacological components for CDDP extractum.展开更多
AIM: To develop an artificial neural network (ANN) model for predicting the resistance index (RI) of taxoids. METHODS: A dataset of 63 experimental data points were compiled from literatures and subdivided into traini...AIM: To develop an artificial neural network (ANN) model for predicting the resistance index (RI) of taxoids. METHODS: A dataset of 63 experimental data points were compiled from literatures and subdivided into training and external test sets randomly. Electrotopological state (E-state) indices were calculated to characterize molecular structure, together with a principle component analysis to reduce the variable space and analyze the relative importance of E-state indices. Back propagation neural network (BPNN) technique was used to build the models. Five-fold cross validation was performed and five models with different compounds composition in training and validation sets were built. The independent external test set was used to evaluate the predictive ability of models. RESULTS: The final model was proved to be good with the cross validation Qcv2 0.62, external testing R2 0.84 and the slope of the regression line through the origin for testing set is 0.9933. CONCLUSION: The QSAR model can predict the RI to a relative nicety, which will aid in the development of new anti-MDR taxoids.展开更多
AIM: Previous studies identify that C7-OH epimers of taxoids are the thermodynamically more stable isomers due to the strong hydrogen bonding of the C7α-OH to the C4α-acetate acyl oxygen. In order to understand the ...AIM: Previous studies identify that C7-OH epimers of taxoids are the thermodynamically more stable isomers due to the strong hydrogen bonding of the C7α-OH to the C4α-acetate acyl oxygen. In order to understand the effects of certain structure modification on taxoids’ interactions with human hepatic cytochromes P450 better, the present study attempts to clarify the identity of the CYPs involved in 7-epi-Taxol, 7-epi-10-Deacetyl-Taxol, and their corresponding C7β-OH isomers metabolism and the underlying mechanisms are also to investigate. METHODS: LC/MS/MS was used to identify the structures of various taxoids metabolites by human liver microsomes. Incubations were conducted with CYP isoform specific inhibitors and recombinant human CYP isoforms to ascribe individual reaction to a single CYP isoform. RESULTS: Two monohydroxylated metabolites (M-1 and M-2) of 7-epi-Taxol were detected by LC/MS, and C3’ (M-1), C6 (M-2) were proposed as the possible hydroxylation sites. 7-epi-10-Deacetyl-Taxol was hydroxylated at C6 by human liver microsomes thus making M-3 as the unique primary metabolite. Chemical inhibition studies and assays with recombinant human CYPs indicated that C3’ (M-1) was generated predominantly by CYP3A4 and C6 (M-2, M-3) by CYP2C8. Compared with the formation of C6-OH-majorepi-Taxol decreased significantlympounds among all chemotherapeutic drugs, Paclitaxel, the Km for C6-hydroxylation of 7-epi-Taxol decreased significantly (13 versus 3 μmol/L, 8.5 versus 1.7 μmol/L) by human liver microsomes and recombinant human CYP2C8. Moreover, the overall metabolism of 7-epi-10-Deacetyl-Taxol increased to 20% in contrast with the low biotransformation rate of 10-deacetyl-Taxol (less than 0.8%). CONCLUSION: These findings suggest the distinct 3D conformation change of taxoids caused by the intromolecular hydrogen bonding may attribute a major role in the substrate recognition by CYP2C8 and lead C-6 of taxoids more accessible to the active site.展开更多
文摘AIM: To provide primarily pharmacokinetic profiles and reveal potentially pharmacological components after oral administration of the extractum for Compund Danshen Dripping Pill (CDDP) in rats, which was mainly composed of protocatechuic aldehyde (PAL), Danshensu (DSS), lithospermic acid A, lithospermic acid B, salvianolic acid D, rosmarinic acid, salvianolic acid B and salvianolic acid A. METHODS: After orally administration of 200 mg CDDP extractum for 1 h, the portal vein blood, the femoral artery blood, the bile and urine samples were separately collected. The gastrointestinal (GI) contents and mucosa were washed with physiological saline and the washing solution was pooled. The whole GI tract was removed and homogenized for analysis. The constituents and concentrations of all above samples were determined by the LC-MS analysis combined with the β-glucuronidase and sulfatase treatment. RESULTS: The investigation after oral administration of CDDP extractum for 1 h in rats indicated that: (1)Most of polyphenolic acids have been degraded into caffeic acid (CA) and DSS in the GI tract. Next, CA could be easily absorbed into blood circulation and a trace of DSS was also transported into the portal vein. The remains of undegraded polyphenolic acids and Danshensu were detained in the GI tract lumen. (2)Part of PAL was firstly oxidized into PAC in GI epithelial cells before absorption into the portal vein. Next, PAC and the rest PAL were further transported into blood circulation. (3)PAC and PAL were distributed in blood circulation in free and conjugated forms after being glucuronidated in the liver and the kidney while only free CA and DSS appeared in vivo. After that, all of these metabolites were gradually secreted into bile and urine. CONCLUSION: The results suggest that DSS, PAL, PAC, CA and their conjugated forms may be potential pharmacological components for CDDP extractum.
文摘AIM: To develop an artificial neural network (ANN) model for predicting the resistance index (RI) of taxoids. METHODS: A dataset of 63 experimental data points were compiled from literatures and subdivided into training and external test sets randomly. Electrotopological state (E-state) indices were calculated to characterize molecular structure, together with a principle component analysis to reduce the variable space and analyze the relative importance of E-state indices. Back propagation neural network (BPNN) technique was used to build the models. Five-fold cross validation was performed and five models with different compounds composition in training and validation sets were built. The independent external test set was used to evaluate the predictive ability of models. RESULTS: The final model was proved to be good with the cross validation Qcv2 0.62, external testing R2 0.84 and the slope of the regression line through the origin for testing set is 0.9933. CONCLUSION: The QSAR model can predict the RI to a relative nicety, which will aid in the development of new anti-MDR taxoids.
文摘AIM: Previous studies identify that C7-OH epimers of taxoids are the thermodynamically more stable isomers due to the strong hydrogen bonding of the C7α-OH to the C4α-acetate acyl oxygen. In order to understand the effects of certain structure modification on taxoids’ interactions with human hepatic cytochromes P450 better, the present study attempts to clarify the identity of the CYPs involved in 7-epi-Taxol, 7-epi-10-Deacetyl-Taxol, and their corresponding C7β-OH isomers metabolism and the underlying mechanisms are also to investigate. METHODS: LC/MS/MS was used to identify the structures of various taxoids metabolites by human liver microsomes. Incubations were conducted with CYP isoform specific inhibitors and recombinant human CYP isoforms to ascribe individual reaction to a single CYP isoform. RESULTS: Two monohydroxylated metabolites (M-1 and M-2) of 7-epi-Taxol were detected by LC/MS, and C3’ (M-1), C6 (M-2) were proposed as the possible hydroxylation sites. 7-epi-10-Deacetyl-Taxol was hydroxylated at C6 by human liver microsomes thus making M-3 as the unique primary metabolite. Chemical inhibition studies and assays with recombinant human CYPs indicated that C3’ (M-1) was generated predominantly by CYP3A4 and C6 (M-2, M-3) by CYP2C8. Compared with the formation of C6-OH-majorepi-Taxol decreased significantlympounds among all chemotherapeutic drugs, Paclitaxel, the Km for C6-hydroxylation of 7-epi-Taxol decreased significantly (13 versus 3 μmol/L, 8.5 versus 1.7 μmol/L) by human liver microsomes and recombinant human CYP2C8. Moreover, the overall metabolism of 7-epi-10-Deacetyl-Taxol increased to 20% in contrast with the low biotransformation rate of 10-deacetyl-Taxol (less than 0.8%). CONCLUSION: These findings suggest the distinct 3D conformation change of taxoids caused by the intromolecular hydrogen bonding may attribute a major role in the substrate recognition by CYP2C8 and lead C-6 of taxoids more accessible to the active site.
