Induction
Contract Research
| Absorption/Transport | Metabolism
| Induction | Physico-Chemical
| Toxicity | Sponsor-Initiated
Protocols
 Induction
of Cytochrome P450 in Human Hepatocytes
Cytochrome P450 induction is a major cause of drug-drug interactions and
information on induction potential of drug candidates is routinely requested
by regulatory agencies (Annu. Rev. Pharmacol. Toxicol. 41:535 [2000];
Xenobiotica 31:539 [2001]) 1,2. We would examine
the cytochrome P450 induction potential of your drug candidates in plated
human hepatocytes in a multiwell format. Induction is measured by catalytic
activity within treated cells versus solvent-only treated cells. Appropriate
positive controls for induction are included. Multiple enzymes are available
for testing, including CYP3A4, CYP2C9, CYP1A2, CYP2C19 and CYP2B6.
Induction of Cytochrome P450 in Animal Livers (ex vivo)
We would examine the cytochrome P450 induction potential of your drug
candidate by testing catalytic activity in livers from preclinical species
treated with your compound. Livers are shipped to us for microsome production
and testing. We would determine protein yield, total P450 content, cytochrome
b5 content, cytochrome c reductase activity and catalytic activities of
CYP1A1/2, CYP2B1/2, CYP2E1, CYP3A and CYP4A. Induction is measured by
catalytic activity within microsomes from treated animals versus vehicle-only
treated animals. Appropriate positive controls for induction are included.
Cytochrome P450 Induction Studies in Human Hepatocytes [ PDF
]
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Lin, J.H. and Lu, A.Y. Interindividual variability
in inhibition and induction of cytochrome P450 enzymes. Annu. Rev.
Pharmacol. Toxicol.41:535 [2001].
-
Worboys, P.D. and Carlile, D.J. Implications and consequences
of enzyme induction on preclinical and clinical development. Xenobiotica
31:539-556 [2001].
Consult the ADME experts at 888.334.5229 or via email
to discuss your needs.
The complete FDA guidance document can be viewed on the web at:
http://www.fda.gov/cder/guidance/clin3.pdf
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