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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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Review Article

Drug-Drug Interactions of P-gp Substrates Unrelated to CYP Metabolism

Author(s): Yumiko Akamine, Norio Yasui-Furukori and Tsukasa Uno*

Volume 20, Issue 2, 2019

Page: [124 - 129] Pages: 6

DOI: 10.2174/1389200219666181003142036

Price: $65

Abstract

Background: Recent US Food and Drug Administration (FDA) draft guidance on pharmacokinetic drugdrug interactions (DDIs) has highlighted the clinical importance of ABC transporters B1 or P-glycoprotein (P-gp), hepatic organic anion-transporting polypeptide transporters and breast cancer resistant protein because of their broad substrate specificity and the potential to be involved in DDIs. This guidance has indicated that digoxin, dabigatran etexilate and fexofenadine are P-gp substrate drugs and has defined P-gp inhibitors as those that increase the AUC of digoxin by ≧1.25-fold in clinical DDI studies. However, when substrate drugs of both CYPs and P-gp are involved in DDIs, it remains that the mechanisms of DDIs will be quite ambiguous in assessing how much the CYPs and/or drug transporters partially contribute to DDIs.

Objective: Since there are no detailed manuscripts that summarizes P-gp interactions unrelated to CYP metabolism, this article reviews the effects of potent P-gp inhibitors and P-gp inducers on the pharmacokinetics of P-gp substrate drugs, including digoxin, talinolol, dabigatran etexilate, and fexofenadine in human studies. In addition, the present outcome were to determine the PK changes caused by DDIs among P-gp substrate drugs without CYP metabolism in human DDI studies.

Conclusion: Our manuscript concludes that the PK changes of the DDIs among P-gp drugs unrelated to CYP metabolism are less likely to be serious, and it appears to be convincing that the absences of clinical effects caused to the PK changes by the P-gp inducers is predominant compared with the excessive effects caused to those by the P-gp inhibitors.

Keywords: P-glycoprotein, drug-drug interaction, digoxin, talinolol, dabigatran, fexofenadine.

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Graphical Abstract

[1]
Thiebaut, F.; Tsuruo, T.; Hamada, H.; Gottesman, M.M.; Pastan, I.; Willingham, M.C. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. USA, 1987, 84, 7735-7738.
[2]
Akamine, Y.; Yasui-Furukori, N.; Ieiri, I.; Uno, T. Psychotropic drug-drug interactions involving P-glycoprotein. CNS Drugs, 2012, 26, 959-973.
[3]
Mudra, D.R.; Desino, K.E.; Desai, P.V. In silico, in vitro and in situ models to assess interplay between CYP3A and P-gp. Curr. Drug Metab., 2011, 12, 750-753.
[4]
Niemi, M.; Tornio, A.; Pasanen, M.K.; Fredrikson, H.; Neuvonen, P.J.; Backman, J.T. Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Eur. J. Clin. Pharmacol., 2006, 62, 463-472.
[5]
U.S. Food and Drug Administration/Center for Drug Evaluation and Research, Guidance for Industry: Drug Interactions Studies - Study Design, Data Analysis, and Clinical Implications. FDA: October 2017; http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf
[6]
Fenner, K.S.; Troutman, M.D.; Kempshall, S.; Cook, J.A.; Ware, J.A.; Smith, D.A.; Lee, C.A. Drug-drug interactions mediated through P-glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin as a probe drug. Clin. Pharmacol. Ther., 2009, 85, 173-181.
[7]
Greiner, B.; Eichelbaum, M.; Fritz, P.; Kreichgauer, H.P.; von Richter, O.; Zundler, J.; Kroemer, H.K. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J. Clin. Invest., 1999, 104, 147-153.
[8]
Gramatté, T.; Oertel, R.; Terhaag, B.; Kirch, W. Direct demonstration of small intestinal secretion and site-dependent absorption of the beta-blocker talinolol in humans. Clin. Pharmacol. Ther., 1996, 59, 541-549.
[9]
Schwarz, U.I.; Gramatté, T.; Krappweis, J.; Berndt, A.; Oertel, R.; von Richter, O.; Kirch, W. Unexpected effect of verapamil on oral bioavailability of the beta-blocker talinolol in humans. Clin. Pharmacol. Ther., 1999, 65, 283-290.
[10]
Westphal, K.; Weinbrenner, A.; Zschiesche, M.; Franke, G.; Knoke, M.; Oertel, R.; Fritz, P.; von Richter, O.; Warzok, R.; Hachenberg, T.; Kauffmann, H.M.; Schrenk, D.; Terhaag, B.; Kroemer, H.K.; Siegmund, W. Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction. Clin. Pharmacol. Ther., 2000, 68, 345-355.
[11]
Kolars, J.C.; Schmiedlin-Ren, P.; Schuetz, J.D.; Fang, C.; Watkins, P.B. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J. Clin. Invest., 1992, 90, 1871-1878.
[12]
Härtter, S.; Sennewald, R.; Nehmiz, G.; Reilly, P. Oral bioavailability of dabigatran etexilate (Pradaxa®) after co-medication with verapamil in healthy subjects. Br. J. Clin. Pharmacol., 2013, 75, 1053-1062.
[13]
Lundahl, J.; Regårdh, C.G.; Edgar, B.; Johnsson, G. Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects. Eur. J. Clin. Pharmacol., 1995, 49, 61-67.
[14]
Härtter, S.; Koenen-Bergmann, M.; Sharma, A.; Nehmiz, G.; Lemke, U.; Timmer, W.; Reilly, P.A. Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin. Br. J. Clin. Pharmacol., 2012, 74, 490-500.
[15]
Cvetkovic, M.; Leake, B.; Fromm, M.F.; Wilkinson, G.R.; Kim, R.B. OATP and Pglycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab. Dispos., 1999, 27, 866-871.
[16]
Lappin, G.; Shishikura, Y.; Jochemsen, R.; Weaver, R.J.; Gesson, C.; Houston, B.; Oosterhuis, B.; Bjerrum, O.J.; Rowland, M.; Garner, C. Pharmacokinetics of fexofenadine: Evaluation of a microdose and assessment of absolute oral bioavailability. Eur. J. Pharm. Sci., 2010, 40, 125-131.
[17]
Nozawa, T.; Imai, K.; Nezu, J.; Tsuji, A.; Tamai, I. Functional characterization of pHsensitive organic anion transporting polypeptide OATP-B in human. J. Pharmacol. Exp. Ther., 2004, 308, 438-445.
[18]
Shimizu, M.; Fuse, K.; Okudaira, K.; Nishigaki, R.; Maeda, K.; Kusuhara, H.; Sugiyama, Y. Contribution of OATP (organic anion-transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab. Dispos., 2005, 33, 1477-1481.
[19]
Tahara, H.; Kusuhara, H.; Fuse, E.; Sugiyama, Y. P-glycoprotein plays a major role in the efflux of fexofenadine in the small intestine and blood-brain barrier, but only a limited role in its biliary excretion. Drug Metab. Dispos., 2005, 33, 963-968.
[20]
Tahara, H.; Kusuhara, H.; Maeda, K.; Koepsell, H.; Fuse, E.; Sugiyama, Y. Inhibition of oat3-mediated renal uptake as a mechanism for drug-drug interaction between fexofenadine and probenecid. Drug Metab. Dispos., 2006, 34, 743-747.
[21]
Matsushima, S.; Maeda, K.; Hayashi, H.; Debori, Y.; Schinkel, A.H.; Schuetz, J.D.; Kusuhara, H.; Sugiyama, Y. Involvement of multiple efflux transporters in hepatic disposition of fexofenadine. Mol. Pharmacol., 2008, 73, 1474-1483.
[22]
Matsushima, S.; Maeda, K.; Inoue, K.; Ohta, K.Y.; Yuasa, H.; Kondo, T.; Nakayama, H.; Horita, S.; Kusuhara, H.; Sugiyama, Y. The inhibition of human multidrug and toxin extrusion1 is involved in the drug-drug interaction caused by cimetidine. Drug Metab. Dispos., 2009, 37, 555-559.
[23]
Tian, X.; Zamek-Gliszczynski, M.J.; Li, J.; Bridges, A.S.; Nezasa, K.; Patel, N.J.; Raub, T.J.; Brouwer, K.L. Multidrug resistance-associated protein 2 is primarily responsible for the biliary excretion of fexofenadine in mice. Drug Metab. Dispos., 2008, 36, 61-64.
[24]
Yasui-Furukori, N.; Uno, T.; Sugawara, K.; Tateishi, T. Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics. Clin. Pharmacol. Ther., 2005, 77, 17-23.
[25]
Shimizu, M.; Uno, T.; Sugawara, K.; Tateishi, T. Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein. Br. J. Clin. Pharmacol., 2006, 61, 538-544.
[26]
Venkatakrishnan, K.; Von Moltke, L.L.; Greenblatt, D.J. Effects of the antifungal agents on oxidative drug metabolism: clinial relevance. Clin. Pharmacokinet., 2000, 38, 111-180.
[27]
Cornwell, M.M.; Pastan, I.; Gottesman, M.M. Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein. J. Biol. Chem., 1987, 262, 2166-2170.
[28]
Shimizu, M.; Uno, T.; Sugawara, K.; Tateishi, T. Effects of single and multiple doses of itraconazole on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein. Br. J. Clin. Pharmacol., 2006, 62, 372-376.
[29]
Uno, T.; Shimizu, M.; Sugawara, K.; Tateishi, T. Lack of dose-dependent effects of itraconazole on the pharmacokinetic interaction with fexofenadine. Drug Metab. Dispos., 2006, 34, 1875-1879.
[30]
Olkkola, K.T.; Ahonen, J.; Neuvonen, P.J. The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth. Analg., 1996, 82, 511-516.
[31]
Greenblatt, D.J.; von Moltke, L.L.; Harmatz, J.S.; Chen, G.; Weemhoff, J.L.; Jen, C.; Kelley, C.J.; LeDuc, B.W.; Zinny, M.A. Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice. Clin. Pharmacol. Ther., 2003, 74, 121-129.
[32]
Hamman, M.A.; Bruce, M.A.; Haehner-Daniels, B.D.; Hall, S.D. The effect of rifampin administration on the disposition of fexofenadine. Clin. Pharmacol. Ther., 2001, 69, 114-121.
[33]
Miura, M.; Uno, T.; Tateishi, T.; Suzuki, T. Pharmacokinetics of fexofenadine enantiomers in healthy subjects. Chirality, 2007, 19, 223-227.
[34]
Akamine, Y.; Miura, M.; Sugawara, S.; Kagaya, H.; Yasui-Furukori, N.; Uno, T. Influence of drug-transporter polymorphisms on the pharmacokinetics of fexofenadine enantiomers. Xenobiotica, 2010, 40, 782-789.
[35]
Kusuhara, H.; Miura, M.; Yasui-Furukori, N.; Yoshida, K.; Akamine, Y.; Yokochi, M.; Fukizawa, S.; Ikejiri, K.; Kanamitsu, K.; Uno, T.; Sugiyama, Y. Effect of coadministration of single and multiple doses of rifampicin on the pharmacokinetics of fexofenadine enantiomers in healthy subjects. Drug Metab. Dispos., 2013, 41, 206-213.
[36]
Akamine, Y.; Miura, M.; Komori, H.; Tamai, I.; Ieiri, I.; Yasui-Furukori, N.; Uno, T. The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion. Drug Metab. Pharmacokinet., 2015, 30, 352-357.
[37]
Akamine, Y.; Miura, M.; Yasui-Furukori, N.; Ieiri, I.; Uno, T. Effects of multiple-dose rifampicin 450 mg on the pharmacokinetics of fexofenadine enantiomers in Japanese volunteers. J. Clin. Pharm. Ther., 2015, 40, 98-103.
[38]
Vavricka, S.R.; Van Montfoort, J.; Ha, H.R.; Meier, P.J.; Fattinger, K. Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology, 2002, 36, 164-172.
[39]
Akamine, Y.; Miura, M.; Yasui-Furukori, N.; Kojima, M.; Uno, T. Carbamazepine differentially affects the pharmacokinetics of fexofenadine enantiomers. Br. J. Clin. Pharmacol., 2012, 73, 478-481.
[40]
Giessmann, T.; May, K.; Modess, C.; Wegner, D.; Hecker, U.; Zschiesche, M.; Dazert, P.; Grube, M.; Schroeder, E.; Warzok, R.; Cascorbi, I.; Kroemer, H.K.; Siegmund, W. Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans. Clin. Pharmacol. Ther., 2004, 76, 192-200.
[41]
Luna-Tortós, C.; Fedrowitz, M.; Löscher, W. Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology, 2008, 55, 1364-1375.
[42]
Zhang, C.; Kwan, P.; Zuo, Z.; Baum, L. In vitro concentration dependent transport of phenytoin and phenobarbital, but not ethosuximide, by human P-glycoprotein. Life Sci., 2010, 86, 899-905.
[43]
Neerati, P.; Ganji, D.; Bedada, S.K. Study on in situ and in vivo absorption kinetics of phenytoin by modulating P-glycoprotein with verapamil in rats. Eur. J. Pharm. Sci., 2011, 44, 27-31.
[44]
Yao, D.; Yang, Z.H.; Liu, L.; Li, J.; Yu, Y.L.; Zhang, L.L.; Pan, X.; Liu, X.D.; Xie, L.; Wang, G.J. Verapamil exerts biphasic modulation on phenobarbital transport across the blood-brainbarrier: Evidence from an in vivo and in vitro study. Naunyn Schmiedebergs Arch. Pharmacol., 2011, 383, 393-402.
[45]
Jing, X.; Liu, X.; Wen, T.; Xie, S.; Yao, D.; Liu, X.; Wang, G.; Xie, L. Combined effects of epileptic seizure and phenobarbital induced overexpression of P-glycoprotein in brain of chemically kindled rats. Br. J. Pharmacol., 2010, 159, 1511-1522.
[46]
Eyal, S.; Lamb, J.G.; Smith-Yockman, M.; Yagen, B.; Fibach, E.; Altschuler, Y.; White, H.S.; Bialer, M. The antiepileptic and anticancer agent, valproic acid, induces P-glycoprotein in human tumour cell lines and in rat liver. Br. J. Pharmacol., 2006, 149, 250-260.
[47]
Lutz, J.D.; Kirby, B.J.; Wang, L.; Song, Q.; Ling, J.; Massetto, B.; Worth, A.; Kearney, B.P.; Mathias, A. Cytochromc P450 3A Induction Predicts P-glycoprotein lnduction; Part l: Establishing lnduction Relationships Using Ascending Dose Rifampin. Clin. Pharmacol. Ther., 2018, 104(6), 1182-1190.
[48]
Wang, J.S.; Ruan, Y.; Taylor, R.M.; Donovan, J.L.; Markowitz, J.S.; DeVane, C.L. The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein. Int. J. Neuropsychopharmacol., 2004, 7, 415-419.
[49]
Wolking, S.; Schaeffeler, E.; Lerche, H.; Schwab, M.; Nies, A.T. Impact of genetic polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on drug disposition and potential clinical implications: Update of the literature. Clin. Pharmacokinet., 2015, 54, 709-735.

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