Inhibition of muraglitazar clearance in pooled human liver microsome B by monoclonal inhibitory antibodies and chemical inhibitors


Percentage Mean Inhibition (n = 3)b
Inhibitory Antibodiesc 1× conc. (2-5 μl/ml)
Chemical Inhibitorsd 1× conc.
CYP2C8 38.2 37.9
CYP2C9 14.7 21.7
CYP2C19 7.6 2.5
CYP2Cs 58.3 NA
CYP2D6 28.7 15.3
CYP3A4 30.1 41.2
All N.A. 98.1e
Total Percentage Inhibition
119.3 (117.1)f
  • N.A., not applicable.

  • a Disappearance of the parent compound was monitored by LC/MS analysis and percentage parent disappearance of muraglitazar was <40% for all incubations.

  • b Percentage Inhibition = (muraglitazar concentration in the presence of inhibitor — muraglitazar concentration in the absence of inhibitor)/(muraglitazar concentration in control — muraglitazar concentration in the absence of inhibitor). Positive control incubations were done in the presence of 1.2 mM NADPH and negative control incubations were done in the absence of NADPH. The variability between runs was less than 15%.

  • c Monoclonal antibodies against human enzymes in mice. The 1× concentrations were based on published results (Gelboin and Krausz, 2006). Inhibition with monoclonal antibodies for CYP1A2, 2A6, 2B6, and 2E1 at 1× concentrations was less than 10%.

  • d Chemical inhibitors were montelukast for CYP2C8, sulfaphenazole for CYP2C9, benzylnirvanol for CYP2C19, quinidine for CYP2D6, ketoconazole for CYP3A4, and 1-aminobenzotriazole for all P450 enzymes; and the respective 1× concentrations used were 3, 10, 1, 1, 1, and 1000 μM. At 5 μM, benzylnirvanol, quinidine, and ketoconazole inhibited 21.4, 21.5, and 39.9% muraglitazar metabolism.

  • e 1-Aminobenzotriazole was used to inhibit all P450 enzymes.

  • f Total percentage inhibition is the sum of inhibition by antibodies or chemical inhibitors for CYP2C8, 2C9, 2C19, 2D6, and 3A4, and the % inhibition in the parentheses is the sum of antibody inhibition for CYP2Cs, 2D6, and 3A4.