Evaluation of in Vivo P-glycoprotein Phenotyping Probes: a Need for Validation

Overview

Journal Clin Pharmacokinet

Specialty Pharmacology

Date 2010 Mar 11

PMID 20214407

Citations 18

Authors

Joseph D Ma

Shirley M Tsunoda

Joseph S Bertino Jr

Meghana Trivedi

Keola K Beale

Anne N Nafziger

Affiliations

Soon will be listed here.

Abstract

Drug transporters are involved in clinically relevant drug-drug interactions. P-glycoprotein (P-gp) is an efflux transporter that displays genetic polymorphism. Phenotyping permits evaluation of real-time, in vivo P-gp activity and P-gp-mediated drug-drug interactions. Digoxin, fexofenadine, talinolol and quinidine are commonly used probe drugs for P-gp phenotyping. Although current regulatory guidance documents highlight methodologies for evaluating transporter-based drug-drug interactions, whether current probe drugs are suitable for phenotyping has not been established, and validation criteria are lacking. This review proposes validation criteria and evaluates P-gp probes to determine probe suitability. Based on these criteria, digoxin, fexofenadine, talinolol and quinidine have limitations to their use and are not recommended for P-gp phenotyping.

Citing Articles

Intestinal P-gp activity is reduced in postmenopausal women under breast cancer therapy.

Ximenez J, de Andrade J, Rocha A, Coelho E, Suarez-Kurtz G, Lanchote V Clin Transl Sci. 2024; 17(1):e13713.

PMID: 38226443 PMC: 10801393. DOI: 10.1111/cts.13713.

Critical Assessment of Phenotyping Cocktails for Clinical Use in an African Context.

Leuschner M, Cromarty A J Pers Med. 2023; 13(7).

PMID: 37511712 PMC: 10381848. DOI: 10.3390/jpm13071098.

Exposure of Fexofenadine, but Not Pseudoephedrine, Is Markedly Decreased by Green Tea Extract in Healthy Volunteers.

Misaka S, Ono Y, Taudte R, Hoier E, Ogata H, Ono T Clin Pharmacol Ther. 2022; 112(3):627-634.

PMID: 35678032 PMC: 9540489. DOI: 10.1002/cpt.2682.

Non-ionic Surfactants as a P-Glycoprotein(P-gp) Efflux Inhibitor for Optimal Drug Delivery-A Concise Outlook.

Rathod S, Desai H, Patil R, Sarolia J AAPS PharmSciTech. 2022; 23(1):55.

PMID: 35043278 DOI: 10.1208/s12249-022-02211-1.

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds.

Darko L, Broni E, Amuzu D, Wilson M, Parry C, Kwofie S Biomedicines. 2021; 9(12).

PMID: 34944612 PMC: 8698941. DOI: 10.3390/biomedicines9121796.

References

Zhou S, Lim L, Chowbay B . Herbal modulation of P-glycoprotein. Drug Metab Rev. 2004; 36(1):57-104. DOI: 10.1081/dmr-120028427. View

Kobayashi M, Saitoh H, Yamaguchi M, Saito T, Fujita H, Suno M . Relationship between loperamide-induced sedative effect and digoxin pharmacokinetics in healthy Japanese subjects. Pharm Res. 2005; 22(3):413-8. DOI: 10.1007/s11095-004-1879-6. View

Kroetz D, Pauli-Magnus C, Hodges L, Huang C, Kawamoto M, Johns S . Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics. 2003; 13(8):481-94. DOI: 10.1097/00008571-200308000-00006. View

Doser K, Meyer B, Nitsche V . Bioequivalence evaluation of two different oral formulations of loperamide (Diarex Lactab vs Imodium capsules). Int J Clin Pharmacol Ther. 1995; 33(8):431-6. View

Ling V . Multidrug resistance: molecular mechanisms and clinical relevance. Cancer Chemother Pharmacol. 1997; 40 Suppl:S3-8. DOI: 10.1007/s002800051053. View

Bartnicka L, Kurzawski M, Drozdzik A, Plonska-Gosciniak E, Gornik W, Drozdzik M . Effect of ABCB1 (MDR1) 3435C >T and 2677G >A,T polymorphisms and P-glycoprotein inhibitors on salivary digoxin secretion in congestive heart failure patients. Pharmacol Rep. 2007; 59(3):323-9. View

El Ela A, Hartter S, Schmitt U, Hiemke C, Spahn-Langguth H, Langguth P . Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds--implications for pharmacokinetics of selected substrates. J Pharm Pharmacol. 2004; 56(8):967-75. DOI: 10.1211/0022357043969. View

Bauer B, Yang X, Hartz A, Olson E, Zhao R, Kalvass J . In vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation. Mol Pharmacol. 2006; 70(4):1212-9. DOI: 10.1124/mol.106.023796. View

Magnusson M, Dahl M, Cederberg J, Karlsson M, Sandstrom R . Pharmacodynamics of carbamazepine-mediated induction of CYP3A4, CYP1A2, and Pgp as assessed by probe substrates midazolam, caffeine, and digoxin. Clin Pharmacol Ther. 2007; 84(1):52-62. DOI: 10.1038/sj.clpt.6100431. View

10.

Miura M, Uno T, Tateishi T, Suzuki T . Pharmacokinetics of fexofenadine enantiomers in healthy subjects. Chirality. 2007; 19(3):223-7. DOI: 10.1002/chir.20370. View

11.

Giessmann T, May K, Modess C, Wegner D, Hecker U, Zschiesche M . Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans. Clin Pharmacol Ther. 2004; 76(3):192-200. DOI: 10.1016/j.clpt.2004.04.011. View

12.

Deferme S, Mols R, Van Driessche W, Augustijns P . Apricot extract inhibits the P-gp-mediated efflux of talinolol. J Pharm Sci. 2002; 91(12):2539-48. DOI: 10.1002/jps.10262. View

13.

Ieiri I, Takane H, Otsubo K . The MDR1 (ABCB1) gene polymorphism and its clinical implications. Clin Pharmacokinet. 2004; 43(9):553-76. DOI: 10.2165/00003088-200443090-00001. View

14.

de Lannoy I, Silverman M . The MDR1 gene product, P-glycoprotein, mediates the transport of the cardiac glycoside, digoxin. Biochem Biophys Res Commun. 1992; 189(1):551-7. DOI: 10.1016/0006-291x(92)91593-f. View

15.

Spahn-Langguth H, Baktir G, Radschuweit A, Okyar A, Terhaag B, Ader P . P-glycoprotein transporters and the gastrointestinal tract: evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound. Int J Clin Pharmacol Ther. 1998; 36(1):16-24. View

16.

Hamman M, BRUCE M, Hall S . The effect of rifampin administration on the disposition of fexofenadine. Clin Pharmacol Ther. 2001; 69(3):114-21. DOI: 10.1067/mcp.2001.113697. View

17.

Ito S, Koren G, Harper P, Silverman M . Energy-dependent transport of digoxin across renal tubular cell monolayers (LLC-PK1). Can J Physiol Pharmacol. 1993; 71(1):40-7. DOI: 10.1139/y93-006. View

18.

Eichelbaum M, Fromm M, Schwab M . Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther Drug Monit. 2004; 26(2):180-5. DOI: 10.1097/00007691-200404000-00017. View

19.

Robbins D, Castles M, Pack D, Bhargava V, Weir S . Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy male volunteers. Biopharm Drug Dispos. 1998; 19(7):455-63. DOI: 10.1002/(sici)1099-081x(199810)19:7<455::aid-bdd130>3.0.co;2-w. View

20.

Bogman K, Zysset Y, Degen L, Hopfgartner G, Gutmann H, Alsenz J . P-glycoprotein and surfactants: effect on intestinal talinolol absorption. Clin Pharmacol Ther. 2005; 77(1):24-32. DOI: 10.1016/j.clpt.2004.09.001. View