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Vol. 30, Issue 7, 795-804, July 2002
Drug Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharma
Company, Newark, Delaware (G.L., J.L., D.C., L.-S.G); Applied
Biotechnology (M.C., T.B., B.S.), Virology Research (C.R.),
Bristol-Myers Squibb Pharma Company, Wilmington, Delaware; Preclinical
Candidate Optimization-Metabolism and Pharmacokinetics,
Bristol-Myers Squibb Company, Wallingford, Connecticut (S.K., M.S.);
Biostatistics and Programming, Bristol-Myers Squibb Company, Princeton,
New Jersey (J.X.); Division of Drug Delivery and Disposition, School of
Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina (G.H., S.J., D.G., R.G., E.L.); XenoTech LLC, Kansas
City, Kansas (A.D., D.M., K.C., A.M., A.P.)
Induction of cytochrome P450 3A4 (CYP3A4) is determined typically
by employing primary culture of human hepatocytes and measuring CYP3A4
mRNA, protein and microsomal activity. Recently a pregnane X receptor
(PXR) reporter gene assay was established to screen CYP3A4 inducers. To
evaluate results from the PXR reporter gene assay with those from the
aforementioned conventional assays, 14 drugs were evaluated for their
ability to induce CYP3A4 and activate PXR. Sandwiched primary cultures
of human hepatocytes from six donors were used and CYP3A4 activity was
assessed by measuring microsomal testosterone 6
-hydroxylase
activity. Hepatic CYP3A4 mRNA and protein levels were also analyzed
using branched DNA technology/Northern blotting and Western
blotting, respectively. In general, PXR activation correlated with the
induction potential observed in human hepatocyte cultures.
Clotrimazole, phenobarbital, rifampin, and sulfinpyrazone highly
activated PXR and increased CYP3A4 activity; carbamazepine,
dexamethasone, dexamethasone-t-butylacetate, phenytoin,
sulfadimidine, and taxol weakly activated PXR and induced CYP3A4
activity, and methotrexate and probenecid showed no marked activation
in either system. Ritonavir and troleandomycin showed marked PXR
activation but no increase (in the case of troleandomycin) or a
significant decrease (in the case of ritonavir) in microsomal CYP3A4
activity. It is concluded that the PXR reporter gene assay is a
reliable and complementary method to assess the CYP3A4 induction potential of drugs and other xenobiotics.
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