Effects of commonly used excipients on the expression of CYP3A4 in colon and liver cells.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Tompkins
Leslie
L
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 21201, USA.
Lynch
Caitlin
C
Haidar
Sam
S
Polli
James
J
Wang
Hongbing
H
D003106:Colon / Q000166:cytology* / Q000187:drug effects*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D005079:Excipients / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D020133:Reverse Transcriptase Polymerase Chain Reaction
D005079:Excipients; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human