Differential effects of the enantiomers of tamsulosin and tolterodine on P-glycoprotein and cytochrome P450 3A4
Language English Country Germany Media print-electronic
Document type Comparative Study, Journal Article
PubMed
27678410
DOI
10.1007/s00210-016-1304-9
PII: 10.1007/s00210-016-1304-9
Knihovny.cz E-resources
- Keywords
- Drug metabolism, Drug transporters, Enantiospecificity, PXR,
- MeSH
- ATP-Binding Cassette Sub-Family B Member 4 MeSH
- Cytochrome P-450 CYP3A genetics metabolism MeSH
- Isomerism MeSH
- Humans MeSH
- LLC-PK1 Cells MeSH
- RNA, Messenger genetics metabolism MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- ATP Binding Cassette Transporter, Subfamily B antagonists & inhibitors genetics metabolism MeSH
- Swine MeSH
- Pregnane X Receptor MeSH
- Promoter Regions, Genetic MeSH
- Gene Expression Regulation, Enzymologic drug effects MeSH
- Receptors, Steroid agonists metabolism MeSH
- Sulfonamides chemistry pharmacology MeSH
- Tamsulosin MeSH
- Tolterodine Tartrate chemistry pharmacology MeSH
- Transfection MeSH
- Up-Regulation MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
- Names of Substances
- ABCB1 protein, human MeSH Browser
- CYP3A4 protein, human MeSH Browser
- Cytochrome P-450 CYP3A MeSH
- cytochrome P450 3A4, mouse MeSH Browser
- RNA, Messenger MeSH
- multidrug resistance protein 3 MeSH Browser
- ATP Binding Cassette Transporter, Subfamily B MeSH
- Pregnane X Receptor MeSH
- Receptors, Steroid MeSH
- Sulfonamides MeSH
- Tamsulosin MeSH
- Tolterodine Tartrate MeSH
The pregnane X receptor (PXR) is a transcription factor regulating P-glycoprotein (P-gp; ABCB1)-mediated transport and cytochrome P450 3A4 (CYP3A4)-mediated metabolism of xenobiotics thereby affecting the pharmacokinetics of many drugs and potentially modulating clinical efficacy. Thus, pharmacokinetic drug-drug interactions can arise from PXR activation. Here, we examined whether the selective α1-adrenoreceptor blocker tamsulosin or the antagonist of muscarinic receptors tolterodine affect PXR-mediated regulation of CYP3A4 and of P-gp at the messenger RNA (mRNA) and protein level in an enantiomer-specific way. In addition, the effect of tamsulosin and tolterodine on P-gp activity was evaluated. We used quantitative real-time PCR, gene reporter assay, western blotting, rhodamine efflux assay, and calcein assay for determination of expression, activity, and inhibition of P-glycoprotein. The studied compounds significantly and concentration-dependently increased PXR activity in the ABCB1-driven luciferase-based reporter gene assay. We observed much stronger induction of ABCB1 mRNA by S-tamsulosin as compared to the R or racemic form. R or racemic form of tolterodine and R-tamsulosin concentration-dependently increased P-gp protein expression; the latter also enhanced P-gp efflux function in a rhodamine-based efflux assay. R-tamsulosin and all forms of tolderodine slightly inhibited P-gp. The effect on CYP3A4 expression followed the same pattern but was much weaker. Taken together, tamsulosin and tolterodine are demonstrated to interfere with P-gp and CYP3A4 regulation in an enantiomer-specific way.
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