Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4

2005 ◽  
Vol 155 (1-2) ◽  
pp. 10-20 ◽  
Author(s):  
Amit S. Kalgutkar ◽  
Kirk R. Henne ◽  
Mary E. Lame ◽  
Alfin D.N. Vaz ◽  
Claire Collin ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Metabolic Activation ◽  
Quinone Imine ◽  
Human Liver Microsomes

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.

METABOLIC ACTIVATION OF PIOGLITAZONE IDENTIFIED FROM RAT AND HUMAN LIVER MICROSOMES AND FRESHLY ISOLATED HEPATOCYTES

2005 ◽  
Vol 33 (6) ◽  
pp. 733-738 ◽  
Author(s):  
T. M. Baughman ◽  
R. A. Graham ◽  
K. Wells-Knecht ◽  
I. S. Silver ◽  
L. O. Tyler ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Metabolic Activation ◽  
Isolated Hepatocytes ◽  
Human Liver Microsomes
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