scholarly journals Metabolism of isorhynchophylline in rats detected by LC-MS

2010 ◽  
Vol 13 (1) ◽  
pp. 27 ◽  
Author(s):  
Wei Wang ◽  
Chao-Mei Ma ◽  
Masao Hattori
Keyword(s):  
Cytochrome P450 ◽  
Chinese Medicine ◽  
Oral Administration ◽  
Rat Liver ◽  
Liver Microsomes ◽  
Circulatory System ◽  
Rat Liver Microsomes ◽  
Specific Inhibition ◽  
Metabolic Fate

PURPOSE This paper investigates the metabolic fate of isorhynchophylline (ISOR) as a main bioactive oxindole alkaloid in the traditional Chinese medicine. METHODS After oral administration of ISOR to rats, plasma, bile, urine and feces were analyzed by LC-MS. Hydroxylation of ISOR and successive glucuronidation proceeded in vitro by incubation with rat liver microsomes. RESULTS ISOR was identified in plasma, 11-hydroxyisorhynchophylline 11-O--D-glucuronide (MI1) and 10-hydroxyisorhynchophylline 10-O--D-glucuronide (MI2) in bile, and free 11-hydroxyisorhynchophylline (MI3) and 10-hydroxyisorhynchophylline (MI4) in urine and feces. Within 24 h, 71.6% of ISOR was excreted into the feces (in 20.0 g) and 13.8% into the urine (in 20.0 ml) of rats after oral administration of 37.5 mg/kg. Monitoring by LC-MS showed that 8.5% of ISOR was metabolized to MI3 and MI4 in a ratio of ca. 1:1. Specific inhibition of CYP isozymes indicated that CYP2D, CYP1A1/2 and CYP2C participate in ISOR hydroxylation. CONCLUSIONS ISOR was involved in the circulatory system after oral administration. Cytochrome P450 (CYP) in rat liver microsomes played a key role in ISOR hydroxylation.

scholarly journals Inhibition and Induction by Poziotinib of Different Rat Cytochrome P450 Enzymes In Vivo and in an In Vitro Cocktail Method

2021 ◽  
Vol 11 ◽  
Author(s):  
Jinhui Wang ◽  
Feifei Chen ◽  
Hui Jiang ◽  
Jia Xu ◽  
Deru Meng ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Rat Liver ◽  
Clinical Investigation ◽  
Liver Microsomes ◽  
Pharmacokinetic Parameters ◽  
Rat Liver Microsomes ◽  
Cytochrome P450 Enzymes ◽  
Significant Difference

Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib is currently under clinical investigation, and understanding its drug-drug interactions is extremely important for its future development and clinical application. The cocktail method is most suitable for evaluating the activity of cytochrome P450 enzymes (CYPs). As poziotinib is partially metabolized by CYPs, cocktail probes are used to study the interaction between drugs metabolized by each CYP subtype. Midazolam, bupropion, dextromethorphan, tolbutamide, chlorzoxazone, phenacetin, and their metabolites were used to examine the effects of poziotinib on the activity of cyp1a2, 2b1, 2d1, 2c11, 2e1, and 3a1/2, respectively. The in vitro experiment was carried out by using rat liver microsomes (RLMs), whereas the in vivo experiment involved the comparison of the pharmacokinetic parameters of the probes after co-administration with poziotinib to rats to those of control rats treated with only probes. UPLC-MS/MS was used to detect the probes and their metabolites in rat plasma and rat liver microsomes. The in vitro results revealed that the half-maximal inhibitory concentration values of bupropion and tolbutamide in RLMs were 8.79 and 20.17 μM, respectively, indicating that poziotinib showed varying degrees of inhibition toward cyp2b1 and cyp2c11. Poziotinib was a competitive inhibitor of cyp2b1 and cyp2c11, with Ki values of 16.18 and 17.66 μM, respectively. No time- or concentration-dependence of inhibition by poziotinib was observed toward cyp2b1 and cyp2c11 in RLMs. Additionally, no obvious inhibitory effects were observed on the activity of cyp1a2, cyp2d1, cyp2e1, and cyp3a1/2. In vivo analysis revealed that bupropion, tolbutamide, phenacetin, and chlorzoxazone showed significantly different pharmacokinetic parameters after administration (p < 0.05); there was no significant difference in the pharmacokinetic parameters of dextromethorphan and midazolam. These results show that poziotinib inhibited cyp2b1 and cyp2c11, but induced cyp1a2 and cyp2e1 in rats. Thus, poziotinib inhibited cyp2b1 and cyp2c11 activity in rats, suggesting the possibility of interactions between poziotinib and these CYP substrates and the need for caution when combining them in clinical settings.

scholarly journals Effects of Wuji Pill with different compatibility on the activity of cytochrome P450 1A2 in rat liver microsomes in vitro

2010 ◽  
Vol 18 (6) ◽  
pp. 586 ◽  
Author(s):  
Xiao-Gang Weng ◽  
Yu-Jie Li ◽  
Qing Yang ◽  
Ri-Xin Liang ◽  
Yi-Wei Wang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
Cytochrome P450 1A2

Use of recombinant human ferrochelatase as a sensitive bioassay for N-alkylprotoporphyrin IX formed after interaction of porphyrinogenic xenobiotics with rat liver microsomes

2000 ◽  
Vol 78 (7) ◽  
pp. 578-581 ◽  
Author(s):  
Jeremy T Gamble ◽  
Simon GW Wong ◽  
Harry A Dailey ◽  
Gerald S Marks
Keyword(s):  
Cytochrome P450 ◽  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
Bioassay System ◽  
Human Cytochrome ◽  
In Vitro Systems ◽  
Layer Chromatography ◽  
Cyp Isozymes

Several porphyrinogenic xenobiotics elicit mechanism-based inactivation of cytochrome P450 (CYP) isozymes, leading to the formation of N-alkylprotoporphyrin IX (N-alkylPP), a potent inhibitor of ferrochelatase, the terminal enzyme in heme biosynthesis. Recognizing their role in experimental porphyria, our long term objective is the establishment of an appropriate in vitro system for the detection and quantification of N-alkylPPs, formed in human liver after the administration of potential porphyrinogenic compounds. In a previous study, we used a combination of thin-layer chromatography and UV-visible spectrophotometry to isolate and identify N-alkylPPs after incubating porphyrinogenic compounds with rat liver microsomes. However, the overall yield of N-alkylPPs was low, and it was concluded that in vitro systems, such as human lymphoblastoid microsomal preparations containing single cDNA-expressed human cytochrome P450 (CYP) isozymes, do not contain sufficient CYP for in vitro studies designed to isolate N-alkylPP. In the present study we demonstrate that purified recombinant human ferrochelatase (FC) provides an extremely sensitive bioassay system for N-alkylPPs and is capable of detecting N-alkylPP in the 10-6nmol range. Therefore, we propose that this bioassay system might allow the use of human lymphoblastoid microsomal preparations containing single cDNA-expressed human CYP isozymes to detect N-alkylPP produced after mechanism-based (catalysis-based) CYP inactivation. If this is found to be correct it will facilitate identification of potentially porphyrinogenic drugs prior to administration to humans.Key words: ferrochelatase, N-alkylprotoporphyrin IX, porphyria, mechanism-based inactivation.

scholarly journals In vitro Effect of Withania somnifera, Mucuna pruriens and Pausinystalia johimbe on Hepatic Cytochrome P450 in Rat

2018 ◽  
Vol 21 (2) ◽  
pp. 118-122
Author(s):  
Rajia Sultana ◽  
Md Zakir Sultan
Keyword(s):  
Cytochrome P450 ◽  
Rat Liver ◽  
Withania Somnifera ◽  
Liver Microsomes ◽  
Mucuna Pruriens ◽  
Cytochrome P450 Enzyme ◽  
Rat Liver Microsomes ◽  
Vitro Effect ◽  
Hepatic Cytochrome

The effect of Withania somnifera, Mucuna pruriens and Pausinystalia johimbe extracts on hepatic cytochrome P450 enzyme CYP3A4 activities was studied using rat liver microsomes. CYP3A4- dependent testosterone 6β-hydroxylation activities were determined by ELISA. In the study, rats were treated with W. somnifera (0.5 g/kg/day), M. pruriens (0.5 g/kg/day) and P. johimbe (0.25 g/kg/day) extracts for 20 days. It was found that W. somnifera, M. pruriens and P. johimbe extracts showed potent to moderate inhibitory effect on CYP3A4 activities in rat liver microsomes, with IC50 values of 18.01 ng/mL, 14.93 ng/mL and 21.03 ng/mL, respectively.Bangladesh Pharmaceutical Journal 21(2): 118-122, 2018

Non-specific inhibition of cytochrome P450 activities by chlorophyllin in human and rat liver microsomes

1995 ◽  
Vol 16 (6) ◽  
pp. 1437-1440 ◽  
Author(s):  
Chul-Ho Yun ◽  
Hye Gwang Jeong ◽  
Jay Woo Jhoun ◽  
F.Peter Guengerich
Keyword(s):  
Cytochrome P450 ◽  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
Specific Inhibition

In vitro metabolism in Sprague–Dawley rat liver microsomes of forsythoside A in different compositions of Shuang–Huang–Lian

Fitoterapia ◽  
2011 ◽  
Vol 82 (8) ◽  
pp. 1222-1230 ◽  
Author(s):  
Wei Zhou ◽  
Liu-qing Di ◽  
Jin-jun Shan ◽  
Xiao-lin Bi ◽  
Le-tian Chen ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
In Vitro Metabolism ◽  
Rat Liver Microsomes ◽  
Sprague Dawley ◽  
Sprague Dawley Rat

scholarly journals In Vitro Characterization of Borneol Metabolites by GC--MS Upon Incubation with Rat Liver Microsomes

2008 ◽  
Vol 46 (5) ◽  
pp. 419-423 ◽  
Author(s):  
R. Zhang ◽  
C.-h. Liu ◽  
T.-l. Huang ◽  
N.-s. Wang ◽  
S.-q. Mi
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
In Vitro Characterization
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