Differential effects of the enantiomers of tamsulosin and tolterodine on P-glycoprotein and cytochrome P450 3A4.
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.
Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
Aneta
A
Doricakova
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Dirk
D
Theile
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Johanna
J
Weiss
Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic. radim.vrzal@email.cz.
Radim
R
Vrzal
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007536:Isomerism; D018374:LLC-PK1 Cells; D051379:Mice; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013552:Swine; D000077409:Tamsulosin; D000068737:Tolterodine Tartrate / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection; D015854:Up-Regulation; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D051544:Cytochrome P-450 CYP3A; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D013449:Sulfonamides; D000077409:Tamsulosin; D000068737:Tolterodine Tartrate; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C513055:ABCB1 protein, human; C095122:multidrug resistance protein 3; C000592551:cytochrome P450 3A4, mouse; C510163:CYP3A4 protein, human
Drug metabolism; Drug transporters; Enantiospecificity; PXR
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