Impact of endogenous esterase activity on in vitro P-glycoprotein profiling of dabigatran etexilate in Caco-2 monolayers

Drug Metabolism and Disposition

Volumn 42, Issue 2, 2014, Pages 250-256

  Ishiguro, Naoki ^a   Kishimoto, Wataru ^a   Volz, Astrid ^b   Ludwig Schwellinger, Eva ^b   Ebner, Thomas ^b   Schaefer, Olaf ^a  

^a NIPPON BOEHRINGER INGELHEIM CO LTD   (Japan)

^b BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

BIBR 0951; BIBR 1087; BIS(4 NITROPHENYL) PHOSPHATE; CARBON 14; CARBOXYLESTERASE; CARBOXYLESTERASE 1; CARBOXYLESTERASE 2; DABIGATRAN; DABIGATRAN ETEXILATE; DRUG METABOLITE; ESTERASE; MULTIDRUG RESISTANCE PROTEIN; PROTEIN INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CELL STRAIN CACO 2; CELL TRANSPORT; COLORECTAL CARCINOMA; CONTROLLED STUDY; DRUG HYDROLYSIS; DRUG STRUCTURE; DRUG TRANSPORT; ENZYME ACTIVITY; HUMAN; HUMAN CELL; IN VITRO STUDY; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; MONOLAYER CULTURE; PERMEABILITY COEFFICIENT; PHYSICAL PARAMETERS; PRIORITY JOURNAL; RADIATION DETECTION; TRANSCYTOSIS;

ANTITHROMBINS; BENZIMIDAZOLES; BIOLOGICAL TRANSPORT; BIOTRANSFORMATION; CACO-2 CELLS; CARBOXYLESTERASE; CARBOXYLIC ESTER HYDROLASES; ENZYME INHIBITORS; HUMANS; HYDROLYSIS; INTESTINES; KINETICS; LIVER; P-GLYCOPROTEIN; PERMEABILITY; PRODRUGS; PYRIDINES;

EID: 84891762128     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.113.053561     Document Type: Article

References (21)

1. Ayrton A and Morgan P (2001) Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica 31:469-497. (Pubitemid 32826389)
2. Bentz J, O'Connor MP, Bednarczyk D, Coleman J, Lee C, Palm J, Pak YA, Perloff ES, Reyner E, and Balimane P, et al. (2013) Variability in P-glycoprotein inhibitory potency (IC50) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria. Drug Metab Dispos 41:1347-1366.
3. Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, and Roth W (2008) The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 36: 386-399. (Pubitemid 351185753)
4. Dresser MJ, Leabman MK, and Giacomini KM (2001) Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J Pharm Sci 90: 397-421. (Pubitemid 32298045)
5. Ebner T, Wagner K, and Wienen W (2010) Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos 38:1567-1575.
6. EMA (2012) Guideline on the Investigation of Drug Interactions. Final CPMP/EWP/560/95, European Medicines Agency, London.
7. Eriksson BI, Dahl OE, Büller HR, Hettiarachchi R, Rosencher N, Bravo ML, Ahnfelt L, Piovella F, Stangier J, and Kälebo P, et al.; BISTRO II Study Group (2005) A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 3:103-111. (Pubitemid 41647122)
8. FDA (2012) Drug Interaction Studies - Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. Draft Guidance. US Food and Drug Administration, Silver Spring, M.D.
9. Fricker G and Miller DS (2002) Relevance of multidrug resistance proteins for intestinal drug absorption in vitro and in vivo. Pharmacol Toxicol 90:5-13. (Pubitemid 34165254)
10. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, and Hillgren KM, et al.; International Transporter Consortium (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215-236.
11. Goh LB, Spears KJ, Yao D, Ayrton A, Morgan P, Roland Wolf C, and Friedberg T (2002) Endogenous drug transporters in in vitro and in vivo models for the prediction of drug disposition in man. Biochem Pharmacol 64:1569-1578. (Pubitemid 35333418)
12. Imai T, Imoto M, Sakamoto H, and Hashimoto M (2005) Identification of esterases expressed in Caco-2 cells and effects of their hydrolyzing activity in predicting human intestinal absorption. Drug Metab Dispos 33:1185-1190. (Pubitemid 41043762)
13. Kusuhara H and Sugiyama Y (2002) Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney. J Control Release 78:43-54. (Pubitemid 34081852)
14. Litman T, Druley TE, Stein WD, and Bates SE (2001) From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance. Cell Mol Life Sci 58: 931-959. (Pubitemid 32652819)
15. Mizuno N, Niwa T, Yotsumoto Y, and Sugiyama Y (2003) Impact of drug transporter studies on drug discovery and development. Pharmacol Rev 55:425-461. (Pubitemid 37013212)
16. Nakanishi T and Tamai I (2012) Genetic polymorphisms of OATP transporters and their impact on intestinal absorption and hepatic disposition of drugs. Drug Metab Pharmacokinet 27: 106-121.
17. Ohtsuki S and Terasaki T (2007) Contribution of carrier-mediated transport systems to the bloodbrain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm Res 24:1745-1758. (Pubitemid 47206624)
18. Ohura K, Nozawa T, Murakami K, and Imai T (2011) Evaluation of transport mechanism of prodrugs and parent drugs formed by intracellular metabolism in Caco-2 cells with modified carboxylesterase activity: temocapril as a model case. J Pharm Sci 100:3985-3994.
19. Ohura K, Sakamoto H, Ninomiya S, and Imai T (2010) Development of a novel system for estimating human intestinal absorption using Caco-2 cells in the absence of esterase activity. Drug Metab Dispos 38:323-331.
20. Stangier J (2008) Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 47:285-295. (Pubitemid 351508116)
21. Starling JJ, Shepard RL, Cao J, Law KL, Norman BH, Kroin JS, Ehlhardt WJ, Baughman TM, Winter MA, and Bell MG, et al. (1997) Pharmacological characterization of LY335979: a potent cyclopropyldibenzosuberane modulator of P-glycoprotein. Adv Enzyme Regul 37:335-347. (Pubitemid 27371567)