scholarly journals Prediction and Quantification of Hepatic Transporter-Mediated Uptake of Pitavastatin Utilizing a Combination of the Relative Activity Factor Approach and Mechanistic Modeling

2018 ◽  
Vol 46 (7) ◽  
pp. 953-963 ◽  
Author(s):  
Pallabi Mitra ◽  
Samantha Weinheimer ◽  
Meeghan Michalewicz ◽  
Mitchell E. Taub
Keyword(s):  
Relative Activity ◽  
Mechanistic Modeling ◽  
Activity Factor ◽  
Hepatic Transporter

scholarly journals Investigation on the metabolic characteristics of isobavachin in Psoralea corylifolia L. (Bu-gu-zhi) and its potential inhibition against human cytochrome P450s and UDP-glucuronosyltransferases

2020 ◽  
Author(s):  
Han Xing ◽  
Jing Yang ◽  
Kaidi Ren ◽  
Zifei Qin ◽  
Peile Wang ◽  
...  
Keyword(s):  
Correlation Analysis ◽  
Kinetic Modelling ◽  
Liver Microsomes ◽  
Hepatic Metabolism ◽  
Relative Activity ◽  
Metabolic Characteristics ◽  
Activity Factor ◽  
Human Cytochrome

Abstract Objectives Isobavachin is a phenolic with anti-osteoporosis activity. This study aimed to explore its metabolic fates in vivo and in vitro, and to investigate the potential drug–drug interactions involving CYPs and UGTs. Methods Metabolites of isobavachin in mice were first identified and characterized. Oxidation and glucuronidation study were performed using liver and intestine microsomes. Reaction phenotyping, activity correlation analysis and relative activity factor approaches were employed to identify the main CYPs and UGTs involved in isobavachin metabolism. Through kinetic modelling, inhibition mechanisms towards CYPs and UGTs were also explored. Key findings Two glucuronides (G1 - G2) and three oxidated metabolites (M1 - M3) were identified in mice. Additionally, isobavachin underwent efficient oxidation and glucuronidation by human liver microsomes and HIM with CLint values from 5.53 to 148.79 μl/min per mg. CYP1A2, 2C19 contributed 11.3% and 17.1% to hepatic metabolism of isobavachin, respectively, with CLint values from 8.75 to 77.33 μl/min per mg. UGT1As displayed CLint values from 10.73 to 202.62 μl/min per mg for glucuronidation. Besides, significant correlation analysis also proved that CYP1A2, 2C19 and UGT1A1, 1A9 were main contributors for the metabolism of isobavachin. Furthermore, mice may be the appropriate animal model for predicting its metabolism in human. Moreover, isobavachin exhibited broad inhibition against CYP2B6, 2C9, 2C19, UGT1A1, 1A9, 2B7 with Ki values from 0.05 to 3.05 μm. Conclusions CYP1A2, 2C19 and UGT1As play an important role in isobavachin metabolism. Isobavachin demonstrated broad-spectrum inhibition of CYPs and UGTs.

IVIVE of Transporter-Mediated Renal Clearance: Relative Expression Factor (REF) vs Relative Activity Factor (RAF) Approach

2021 ◽  
pp. DMD-AR-2021-000367
Author(s):  
Aditya R. Kumar ◽  
Bhagwat Prasad ◽  
Deepak Kumar Bhatt ◽  
Sumathy Mathialagan ◽  
Manthena V. S. Varma ◽  
...  
Keyword(s):  
Renal Clearance ◽  
Relative Activity ◽  
Relative Expression ◽  
Activity Factor

Using human recombinant UDP-glucuronosyltransferase isoforms and a relative activity factor approach to model total body clearance of laropiprant (MK-0524) in humans

Xenobiotica ◽  
2013 ◽  
Vol 43 (12) ◽  
pp. 1027-1036 ◽  
Author(s):  
Christopher R. Gibson ◽  
Ping Lu ◽  
Cheri Maciolek ◽  
Christen Wudarski ◽  
Zoe Barter ◽  
...  
Keyword(s):  
Total Body Clearance ◽  
Relative Activity ◽  
Activity Factor ◽  
Udp Glucuronosyltransferase ◽  
Total Body ◽  
Body Clearance
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