Evaluation of P450 Inhibition and Induction by Artemisinin Antimalarials in Human Liver Microsomes and Primary Human Hepatocytes

2012 ◽  
Vol 40 (9) ◽  
pp. 1757-1764 ◽  
Author(s):  
Jie Xing ◽  
Brian J. Kirby ◽  
Dale Whittington ◽  
Yakun Wan ◽  
David R. Goodlett
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Hepatocytes ◽  
Human Liver Microsomes ◽  
Primary Human Hepatocytes

In vitro metabolism of a new cardioprotective agent, KR-33028 in the human liver microsomes and cryopreserved human hepatocytes

2005 ◽  
Vol 28 (11) ◽  
pp. 1287-1292 ◽  
Author(s):  
Hyojin Kim ◽  
Yune -Jung Yoon ◽  
Hyunmi Kim ◽  
Eun -Young Cha ◽  
Hye Suk Lee ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Hepatocytes ◽  
Human Liver Microsomes ◽  
In Vitro Metabolism

scholarly journals Metabolic Activation of Pradefovir by CYP3A4 and Its Potential as an Inhibitor or Inducer

2006 ◽  
Vol 50 (9) ◽  
pp. 2926-2931 ◽  
Author(s):  
Chin-chung Lin ◽  
Che Fang ◽  
Salete Benetton ◽  
Gui-fen Xu ◽  
Li-Tain Yeh
Keyword(s):  
Human Liver ◽  
Primary Cultures ◽  
Liver Microsomes ◽  
Metabolic Activation ◽  
Intrinsic Clearance ◽  
Human Hepatocytes ◽  
Human Liver Microsomes ◽  
Predominant Role ◽  
Oral Dosing

ABSTRACT Metabolic activation of pradefovir to 9-(2-phosphonylmethoxyethyl)adenine (PMEA) was evaluated by using cDNA-expressed CYP isozymes in portal vein-cannulated rats following oral administration and in human liver microsomes. The enzyme induction potential of pradefovir was evaluated in rats following multiple oral dosing and in primary cultures of human hepatocytes. The results indicated that CYP3A4 is the only cDNA-expressed CYP isozyme catalyzing the conversion of pradefovir to PMEA. Pradefovir was converted to PMEA in human liver microsomes with a Km of 60 μM, a maximum rate of metabolism of 228 pmol/min/mg protein, and an intrinsic clearance of about 359 ml/min. Addition of ketoconazole and monoclonal antibody 3A4 significantly inhibits the conversion of pradefovir to PMEA in human liver microsomes, suggesting the predominant role of CYP3A4 in the metabolic activation of pradefovir. Pradefovir at 0.2, 2, and 20 μM was neither a direct inhibitor nor a mechanism-based inhibitor of CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1, and CYP1A2 in human liver microsomes. In rats, the liver was the site of metabolic activation of pradefovir, whereas the small intestine did not play a significant role in the metabolic conversion of pradefovir to PMEA. Daily oral dosing (300 mg/kg of body weight) to rats for 8 days showed that pradefovir was not an inducer of P450 enzymes in rats. Furthermore, pradefovir at 10 μg/ml was not an inducer of either CYP1A2 or CYP3A4/5 in primary cultures of human hepatocytes.

scholarly journals Mertansine Inhibits mRNA Expression and Enzyme Activities of Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyltransferases in Human Hepatocytes and Liver Microsomes

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 220
Author(s):  
Won-Gu Choi ◽  
Ria Park ◽  
Dong Kyun Kim ◽  
Yongho Shin ◽  
Yong-Yeon Cho ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Enzyme Activities ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Hepatocytes ◽  
Cytochrome P450s ◽  
Human Liver Microsomes ◽  
Mrna Levels ◽  
Tubulin Inhibitor

Mertansine, a tubulin inhibitor, is used as the cytotoxic component of antibody–drug conjugates (ADCs) for cancer therapy. The effects of mertansine on uridine 5′-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes and its effects on the mRNA expression of cytochrome P450s (CYPs) and UGTs in human hepatocytes were evaluated to assess the potential for drug–drug interactions (DDIs). Mertansine potently inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-β-glucuronidation, and UGT1A4-catalyzed trifluoperazine N-β-d-glucuronidation, with Ki values of 13.5 µM, 4.3 µM, and 21.2 µM, respectively, but no inhibition of UGT1A6, UGT1A9, and UGT2B7 enzyme activities was observed in human liver microsomes. A 48 h treatment of mertansine (1.25–2500 nM) in human hepatocytes resulted in the dose-dependent suppression of mRNA levels of CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, UGT1A1, and UGT1A9, with IC50 values of 93.7 ± 109.1, 36.8 ± 18.3, 160.6 ± 167.4, 32.1 ± 14.9, 578.4 ± 452.0, 539.5 ± 233.4, 856.7 ± 781.9, and 54.1 ± 29.1 nM, respectively, and decreased the activities of CYP1A2-mediated phenacetin O-deethylase, CYP2B6-mediated bupropion hydroxylase, and CYP3A4-mediated midazolam 1′-hydroxylase. These in vitro DDI potentials of mertansine with CYP1A2, CYP2B6, CYP2C8/9/19, CYP3A4, UGT1A1, and UGT1A9 substrates suggest that it is necessary to carefully characterize the DDI potentials of ADC candidates with mertansine as a payload in the clinic.

Sign in / Sign up

Export Citation Format

Share Document