Study on metabolic dynamics,metabolic enzyme phenotype and species difference of hepatic and intestinal microsome of psoralidin / 中国中药杂志

This study aims to investigate metabolic activities of psoralidin in human liver microsomes( HLM) and intestinal microsomes( HIM),and to identify cytochrome P450 enzymes( CYPs) and UDP-glucuronosyl transferases( UGTs) involved in psoralidin metabolism as well as species differences in the in vitro metabolism of psoralen. First,after incubation serial of psoralidin solutions with nicotinamide adenine dinucleotide phosphate( NADPH) or uridine 5'-diphosphate-glucuronic acid( UDPGA)-supplemented HLM or HIM,two oxidic products( M1 and M2) and two conjugated glucuronides( G1 and G2) were produced in HLM-mediated incubation system,while only M1 and G1 were detected in HIM-supplemented system. The CLintfor M1 in HLM and HIM were 104. 3,and57. 6 μL·min~(-1)·mg~(-1),respectively,while those for G1 were 543. 3,and 75. 9 μL·min~(-1)·mg~(-1),respectively. Furthermore,reaction phenotyping was performed to identify the main contributors to psoralidin metabolism after incubation of psoralidin with NADPH-supplemented twelve CYP isozymes( or UDPGA-supplemented twelve UGT enzymes),respectively. The results showed that CYP1 A1( 39. 5 μL·min~(-1)·mg~(-1)),CYP2 C8( 88. 0 μL·min~(-1)·mg~(-1)),CYP2 C19( 166. 7 μL·min~(-1)·mg~(-1)),and CYP2 D6( 9. 1 μL·min~(-1)·mg~(-1)) were identified as the main CYP isoforms for M1,whereas CYP2 C19( 42. 0 μL·min~(-1)·mg~(-1)) participated more in producing M2. In addition,UGT1 A1( 1 184. 4 μL·min~(-1)·mg~(-1)),UGT1 A7( 922. 8 μL·min~(-1)·mg~(-1)),UGT1 A8( 133. 0 μL·min~(-1)·mg~(-1)),UGT1 A9( 348. 6 μL·min~(-1)·mg~(-1)) and UGT2 B7( 118. 7 μL·min~(-1)·mg~(-1)) played important roles in the generation of G1,while UGT1 A9( 111. 3 μL·min~(-1)·mg~(-1)) was regarded as the key UGT isozyme for G2. Moreover,different concentrations of psoralidin were incubated with monkey liver microsomes( MkLM),rat liver microsomes( RLM),mice liver microsomes( MLM),dog liver microsomes( DLM) and mini-pig liver microsomes( MpLM),respectively. The obtained CLintwere used to evaluate the species differences.Phase Ⅰ metabolism and glucuronidation of psoralidinby liver microsomes showed significant species differences. In general,psoralidin underwent efficient hepatic and intestinal metabolisms. CYP1 A1,CYP2 C8,CYP2 C19,CYP2 D6 and UGT1 A1,UGT1 A7,UGT1 A8,UGT1 A9,UGT2 B7 were identified as the main contributors responsible for phase Ⅰ metabolism and glucuronidation,respectively. Rat and mini-pig were considered as the appropriate model animals to investigate phase Ⅰ metabolism and glucuronidation,respectively.

Association of UGTs, ABCC2, SLCO1B1 and IMPDH Gene Polymorphisms with the Metabolism and Adverse Reactions of Mycophenolate Ester in Renal Transplant Patients / 中国药学杂志

OBJECTIVE: To investigate the association of UGTs, ABCC2, SLCO1B1 and IMPDH gene polymorphisms with metabolism and adverse reaction of mycophenolate ester in early renal transplant recipients. METHODS: A total of 233 patients who received tacrolimus+glucocorticoid+mycophenolate mofetil treatment after living kidney transplantation were enrolled. Single nucleotide polymorphisms of 13 gene were detected by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Kruskal-Wallis H test was used to analyze the effect of 13 single nucleotide polymorphisms on the exposure/dose (AUC/D) and adverse reactions of mycophenolic acid in early recipients after renal transplantation. RESULTS: The AUC/D of mycophenolic acid in UGT2B7 802C>T CC and CT genotype recipients was (36.03±16.19) and (38.06±15.41) mg•h•L-1/g•d-1, which was significantly lower than that in TT genotype recipients (43.63±15.10) mg•h•L-1/g•d-1 (P=0.021). The AUC/D of mycophenolic acid in SLCO1B1 521T > C TT, TC and CC genotype recipients were (36.78±15.70), (41.27±12.92) and (45.10±21.32) mg•h•L-1/g•d-1, respectively. There was significant difference between groups (P=0.036). There was no significant difference between 13 single nucleotide polymorphisms and adverse reactions (P>0.05). CONCLUSION: The AUC/D of mycophenolic acid in early recipients after kidney transplantation are associated with the polymorphism of UGT2B7 802C > T and SLCO1B1 521T > C.

A new 3, 4-seco-lanostane triterpenoid from a marine-derived fungus Ascotricha sp. ZJ-M-5 / 药学学报

To study the secondary metabolites of a marine-derived fungus Ascotricha sp. ZJ-M-5, several chromatographic methods including macroporous resin, silica gel, ODS and Sephadex LH-20 were used to isolate the compounds, and their structures were elucidated on the basis of physicochemical properties and spectroscopic methods. Ten compounds were obtained and identified as ascotrichic acid B (1), (3R)-6-hydroxymellein (2), beta-carboline (3), (22E, 24R)-ergosta-7, 22-diene-3beta, 5alpha, 6beta-triol (4), (22E, 24R)-ergosta-7, 22-diene-3beta, 5alpha, 6beta, 9alpha-tetraol (5), cyclo (Leu-Pro) (6), cyclo (Ile-Leu) (7), cyclo (Pro-Val) (8), cyclo (Pro-Gly) (9), and cyclo (Hpro-Ala) (10). Among them, compound 1 is a new 3, 4-seco-lanostane triterpenoid which has been isolated from the filamentous fungi for the first time, and compounds 2-10 are firstly isolated from Ascotricha genus.