Abstract
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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References
Albermann N, Schmitz-Winnenthal FH, Z’Graggen K, Volk C, Hoffmann MM, Haefeli WE, Weiss J (2005) Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem Pharmacol 70:949–958. doi:10.1016/j.bcp.2005.06.018
Andersson KE (2000) Mode of action of alpha1-adrenoreceptor antagonists in the treatment of lower urinary tract symptoms. BJU Int 85(Suppl 2):12–18
Andersson KE (2002) Alpha-adrenoceptors and benign prostatic hyperplasia: basic principles for treatment with alpha-adrenoceptor antagonists. World J Urol 19:390–396
Andersson KE (2004) Antimuscarinics for treatment of overactive bladder. Lancet Neurol 3:46–53
Blaschke G, Kraft HP, Fickentscher K, Kohler F (1979) Chromatographic separation of racemic thalidomide and teratogenic activity of its enantiomers (author’s transl. Arzneimittelforschung 29:1640–1642
Boesch D, Gaveriaux C, Jachez B, Pourtier-Manzanedo A, Bollinger P, Loor F (1991) In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. Cancer Res 51:4226–4233
Breidenbach T, Hoffmann MW, Becker T, Schlitt H, Klempnauer J (2000) Drug interaction of St John’s wort with cyclosporin. Lancet 355:1912
Brynne N, Stahl MM, Hallen B, Edlund PO, Palmer L, Hoglund P, Gabrielsson J (1997) Pharmacokinetics and pharmacodynamics of tolterodine in man: a new drug for the treatment of urinary bladder overactivity. Int J Clin Pharmacol Ther 35:287–295
Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L (1999) Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity. Br J Clin Pharmacol 48:564–572
Callegari E et al (2011) A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder. Br J Clin Pharmacol 72:235–246. doi:10.1111/j.1365-2125.2011.03961.x
Chapple CR (1996) Selective alpha 1-adrenoceptor antagonists in benign prostatic hyperplasia: rationale and clinical experience. Eur Urol 29:129–144
Chen YK, Tang Y, Guo CX, Wang JH, Boral D, Nie DT (2012) Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters. Biochem Pharmacol 83:1112–1126. doi:10.1016/j.bcp.2012.01.030
Covyeou JA, Jackson CW (2007) Hyponatremia associated with escitalopram. N Engl J Med 356:94–95. doi:10.1056/NEJMc062840
Delfosse V et al (2015) Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds. Nat Commun 6:8089. doi:10.1038/ncomms9089
Dmochowski RR, Appell RA (2000) Advancements in pharmacologic management of the overactive bladder. Urology 56:41–49
Eap CB et al (2007) Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther 81:719–728. doi:10.1038/sj.clpt.6100120
Franco-Salinas G, de la Rosette JJ, Michel MC (2010) Pharmacokinetics and pharmacodynamics of tamsulosin in its modified-release and oral controlled absorption system formulations. Clin Pharmacokinet 49:177–188. doi:10.2165/11317580-000000000-00000
Geick A, Eichelbaum M, Burk O (2001) Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276:14581–14587. doi:10.1074/jbc.M010173200
Heger W, Schmahl HJ, Klug S, Felies A, Nau H, Merker HJ, Neubert D (1994) Embryotoxic effects of thalidomide derivatives in the non-human primate Callithrix jacchus. IV. Teratogenicity of micrograms/kg doses of the EM12 enantiomers. Teratog Carcinog Mutagen 14:115–122
Hills CJ, Winter SA, Balfour JA (1998) Tolterodine. Drugs 55:813–820 discussion 821-812
Hua TC et al (2004) Effect of duloxetine on tolterodine pharmacokinetics in healthy volunteers. Br J Clin Pharmacol 57:652–656. doi:10.1111/j.1365-2125.2004.02068.x
Kamimura H et al. (1998) Identification of cytochrome P450 isozymes involved in metabolism of the alpha1-adrenoceptor blocker tamsulosin in human liver microsomes Xenobiotica; the fate of foreign compounds in biological systems 28:909–922 doi:10.1080/004982598238985
Kawabe K, Moriyama N, Yamada S, Taniguchi N (1994) Rationale for the use of alpha-blockers in the treatment of benign prostatic hyperplasia (BPH. Int J Urol 1:203–211
Kim SO, Hwang EC, KJ O, Kwon D, Park K, Ryu SB (2011) Efficacy and safety of combined therapy with tamsulosin and tolterodine in female patients with a maximal flow rate less than 12 ml/s. Int Urogynecol J 22:1287–1291. doi:10.1007/s00192-011-1453-9
Lv JL, Tang QL (2013) Tamsulosin and tolterodine in the medical expulsive therapy for intramural ureteral stones with vesical irritability: a prospective randomized study. Urolithiasis 41:417–421. doi:10.1007/s00240-013-0599-y
Lyseng-Williamson KA, Jarvis B, Wagstaff AJ (2002) Tamsulosin—an update of its role in the management of lower urinary tract symptoms. Drugs 62:135–167. doi:10.2165/00003495-200262010-00006
Matsushima H, Kamimura H, Soeishi Y, Watanabe T, Higuchi S, Tsunoo M (1998) Pharmacokinetics and plasma protein binding of tamsulosin hydrochloride in rats, dogs, and humans. Drug Metab Dispos 26:240–245
Nilvebrant L, Gillberg PG, Sparf B (1997a) Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine. Pharmacol Toxicol 81:169–172
Nilvebrant L, Hallen B, Larsson G (1997b) Tolterodine—a new bladder selective muscarinic receptor antagonist: preclinical pharmacological and clinical data. Life Sci 60:1129–1136
Novotna A, Kamenickova A, Pecova M, Korhonova M, Bartonkova I, Dvorak Z (2014) Profiling of enantiopure drugs towards aryl hydrocarbon (AhR), glucocorticoid (GR) and pregnane X (PXR) receptors in human reporter cell lines. Chem Biol Interact 208:64–76. doi:10.1016/j.cbi.2013.11.018
Ouslander JG (2004) Management of overactive bladder. N Engl J Med 350:786–799. doi:10.1056/NEJMra032662
Pahlman I, Gozzi P (1999) Serum protein binding of tolterodine and its major metabolites in humans and several animal species. Biopharm Drug Dispos 20:91–99
Peters T, Lindenmaier H, Haefeli WE, Weiss J (2006) Interaction of the mitotic kinesin Eg5 inhibitor monastrol with P-glycoprotein Naunyn Schmiedeberg’s. Arch Pharmacol 372:291–299. doi:10.1007/s00210-005-0022-5
Postlind H, Danielson A, Lindgren A, Andersson SH (1998) Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3 A in human liver microsomes. Drug Metab Dispos 26:289–293
Puppo P (2001) Do we know everything about alpha-blockade in the management of lower urinary tract symptoms? Eur Urol 39(Suppl 2):38–41
Randle LE, Sathish JG, Kitteringham NR, Macdonald I, Williams DP, Park BK (2008) Alpha(1)-adrenoceptor antagonists prevent paracetamol-induced hepatotoxicity in mice. Br J Pharmacol 153:820–830. doi:10.1038/sj.bjp.0707620
Richardson CD, Donatucci CF, Page SO, Wilson KH, Schwinn DA (1997) Pharmacology of tamsulosin: saturation-binding isotherms and competition analysis using cloned alpha 1-adrenergic receptor subtypes. Prostate 33:55–59
Rigalli JP et al. (2012) Regulation of biotransformation systems and ABC transporters by benznidazole in HepG2 cells: involvement of pregnane X-receptor PLoS neglected tropical diseases 6:e1951 doi:10.1371/journal.pntd.0001951
Schinkel AH, Wagenaar E, Mol CA, van Deemter L (1996) P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97:2517–2524. doi:10.1172/JCI118699
Scott AK (1993) Stereoisomers and drug toxicity. The value of single stereoisomer therapy. Drug Saf 8:149–159
Sivalingam S, Streeper NM, Sehgal PD, Sninsky BC, Best SL, Nakada SY (2016) Does combination therapy with tamsulosin and tolterodine improve ureteral stent discomfort compared with tamsulosin alone? A Double-Blind, Randomized, Controlled Trial. J Urol 195:385–390. doi:10.1016/j.juro.2015.08.104
Smith SW (2009) Chiral toxicology: it’s the same thing...Only different. Toxicol Sci 110:4–30. doi:10.1093/toxsci/kfp097
Storch CH, Theile D, Lindenmaier H, Haefeli WE, Weiss J (2007) Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein. Biochem Pharmacol 73:1573–1581. doi:10.1016/j.bcp.2007.01.027
Troost J, Tatami S, Tsuda Y, Mattheus M, Mehlburger L, Wein M, Michel MC (2011) Effects of strong CYP2D6 and 3 A4 inhibitors, paroxetine and ketoconazole, on the pharmacokinetics and cardiovascular safety of tamsulosin. Br J Clin Pharmacol 72:247–256. doi:10.1111/j.1365-2125.2011.03988.x
Tucker GT (2000) Chiral switches. Lancet 355:1085–1087. doi:10.1016/S0140-6736(00)02047-X
Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE (2003) Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther 305:197–204. doi:10.1124/jpet.102.046532
Weiss J, Weis N, Ketabi-Kiyanvash N, Storch CH, Haefeli WE (2008) Comparison of the induction of P-glycoprotein activity by nucleotide, nucleoside, and non-nucleoside reverse transcriptase inhibitors. Eur J Pharmacol 579:104–109. doi:10.1016/j.ejphar.2007.11.007
Zhang L, Zhang YD, Strong JM, Reynolds KS, Huang SM (2008) A regulatory viewpoint on transporter-based drug interactions Xenobiotica; the fate of foreign compounds in biological systems 38:709–724 doi:10.1080/00498250802017715
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This work was supported by the grant from Gran Agency of Czech Republic GACR 13-01809S and by student project of the Palacky University in Olomouc, IGA PrF-2016-003.
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Aneta Doricakova and Dirk Theile contributed equally to this work. Johanna Weiss and Radim Vrzal contributed equally to this work.
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Doricakova, A., Theile, D., Weiss, J. et al. Differential effects of the enantiomers of tamsulosin and tolterodine on P-glycoprotein and cytochrome P450 3A4. Naunyn-Schmiedeberg's Arch Pharmacol 390, 49–59 (2017). https://doi.org/10.1007/s00210-016-1304-9
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DOI: https://doi.org/10.1007/s00210-016-1304-9