Effects of Commonly Used Excipients on the Expression of CYP3A4 in Colon and Liver Cells
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The objective of this investigation was to assess whether common pharmaceutical excipients regulate the expression of drug-metabolizing enzymes in human colon and liver cells.
Nineteen commonly used excipients were evaluated using a panel of experiments including cell-based human PXR activation assays, real-time RT-PCR assays for CYP3A4 mRNA expression, and immunoblot analysis of CYP3A4 protein expression in immortalized human liver cells (HepG2 and Fa2N4), human primary hepatocytes, and the intestinal LS174T cell models.
No excipient activated human PXR or practically induced CYP3A4. However, three excipients (polysorbate 80, pregelatinized starch, and hydroxypropyl methylcellulose) tended to decrease mRNA and protein expression across experimental models.
This study represents the first investigation of the potential role of excipients in the expression of drug-metabolizing enzymes. Findings imply that some excipients may hold potential for excipient-drug interactions by repression of CYP3A4 expression.
KEY WORDSexcipients CYP3A4 PXR induction repression
cytochrome P450 3A4
dicalcium phosphate dehydrate
polyethylene glycol 3350
pregnane X receptor
amorphous fumed silicon dioxide
sodium lauryl sulfate
sodium starch glycolate
The authors thank Dr. Steve Kliewer (University of Texas, Southwestern Medical Center, Dallas, TX) for providing the pSG5-hPXR expression vector. Human liver tissues were procured with the assistance of Jennifer Fuhrman from the University of Maryland Medical Center (Baltimore, MD). This research was partly supported by National Institute of Health Grant (R01, DK061652).
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