Z-338 - Cerep

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Anti-CYP2C8 Anti-CYP3A4 Z-338 Table 4 Summary of the relative contribution of CYP2C8 and CYP3A4 to the metabolism of Z-338 by human liver microsomes Clearance Specific Content Adjusted Clearance Enzyme Relative (µL/min/pmol (pmol p-450/mg (µL/ min /mg System Contribution P450) protein) protein) rCYP2C8 0.0833 64 5.33 88% Anti-CYP2C8 Anti-CYP3A4 ID951551 0 10 20 30 40 50 60 70 80 90 Inhibition (%) rCYP3A4 0.00679 108 0.733 12% r: recombinant Clearance = (Vmax ÷ Km) Specific content values are from Rodrigues, 1999. Adjusted Clearance (µL/mg protein/min) = Clearance (µL/min/pmol P450) x Specific Content (pmol/mg protein) Relative Contribution (%) = (Adjusted Clearance (µL/ min /mg protein) ÷ Total Adjusted Clearance (µL/min /mg protein)) x 100% Fig. 7 Percent inhibition for Z-338 and ID951551when incubated with human liver microsomes pretreated with polyclonal antibodies against CYP2C8 and CYP3A4
Conclusion Z-338 is predominantly metabolized to Z-338 glucuronide by UGT1A8 and UGT1A9 (probably UGT1A9>>UGT1A8). Z-338 is also catalyzed to deisopropyl metabolite by mainly CYP2C8. Z-338 showed little inhibition on CYP2C8 activities, which is significantly less than by its analog, ID951551. This may be based on the fact that its major metabolic pathway being glucuronidation rather than oxidation. Z-338 is considered unlikely to cause significant drugdrug interactions when coadministered with CYP substrates at clinically effective doses.
Page 1 and 2: Involvement of CYP2C8 and UGT1A9 in
Page 3 and 4: CYP2C8 (>>CYP3A4 or 1A1) MeO O N H
Page 5 and 6: Method: In vitro inhibition study T
Page 7 and 8: CYP1A1 CYP1A2 CYP2A6 CYP2B6 CYP2C8
Page 9 and 10: Rate (pmol/min/mg protein) 160 140
Page 11: Table 3 Inhibition constants (K i v

Z-338 - Cerep

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