The pharmacokinetics and hepatic disposition of repaglinide in pigs: Mechanistic modeling of metabolism and transport

Molecular Pharmaceutics

Volumn 9, Issue 4, 2012, Pages 823-841

  Sjögren, Erik ^a   Bredberg, Ulf ^b   Lennernäs, Hans ^a  

^a UPPSALA UNIVERSITY   (Sweden)

^b ASTRAZENECA R AND D   (Sweden)

Author keywords

drug drug interaction; hepatic disposition; hepatocytes; metabolism; physiologically based pharmacokinetic (PBPK) modeling; transport

Indexed keywords

BEZAFIBRATE; DICLOFENAC; KETOCONAZOLE; QUININE; REPAGLINIDE; TRIMETHOPRIM;

ACTIVE TRANSPORT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BILE; CONTROLLED STUDY; DRUG DISPOSITION; DRUG GLUCURONIDATION; DRUG METABOLISM; DRUG TRANSPORT; ENZYME KINETICS; EXPERIMENTAL PIG; IN VITRO STUDY; IN VIVO STUDY; LIVER CELL; LIVER CLEARANCE; LIVER METABOLISM; LIVER MICROSOME; MALE; NONBIOLOGICAL MODEL; NONHUMAN; PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL; PRIORITY JOURNAL; URINE;

ANIMALS; BIOLOGICAL TRANSPORT; CARBAMATES; DRUG INTERACTIONS; HEPATOCYTES; LIVER; MICROSOMES, LIVER; PIPERIDINES; SWINE;

EID: 84859358235     PISSN: 15438384     EISSN: 15438392     Source Type: Journal    
DOI: 10.1021/mp200218p     Document Type: Article

References (62)

1. Obach, R. S. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes Drug Metab. Dispos. 1999, 27 (11) 1350-9
2. Lin, J. H.; Lu, A. Y. Role of pharmacokinetics and metabolism in drug discovery and development Pharmacol. Rev. 1997, 49 (4) 403-49 (Pubitemid 28030947)
3. Mizuno, N.; Niwa, T.; Yotsumoto, Y.; Sugiyama, Y. Impact of drug transporter studies on drug discovery and development Pharmacol. Rev. 2003, 55 (3) 425-61 (Pubitemid 37013212)
4. Shitara, Y.; Horie, T.; Sugiyama, Y. Transporters as a determinant of drug clearance and tissue distribution Eur. J. Pharm. Sci. 2006, 27 (5) 425-46 (Pubitemid 43363338)
5. Chandra, P.; Brouwer, K. L. The complexities of hepatic drug transport: current knowledge and emerging concepts Pharm. Res. 2004, 21 (5) 719-35 (Pubitemid 39011292)
6. Giacomini, K. M.; Huang, S. M.; Tweedie, D. J.; Benet, L. Z.; Brouwer, K. L.; Chu, X.; Dahlin, A.; Evers, R.; Fischer, V.; Hillgren, K. M.; Hoffmaster, K. A.; Ishikawa, T.; Keppler, D.; Kim, R. B.; Lee, C. A.; Niemi, M.; Polli, J. W.; Sugiyama, Y.; Swaan, P. W.; Ware, J. A.; Wright, S. H.; Yee, S. W.; Zamek-Gliszczynski, M. J.; Zhang, L. Membrane transporters in drug development Nat. Rev. Drug Discovery 2010, 9 (3) 215-36
7. McGinnity, D. F.; Soars, M. G.; Urbanowicz, R. A.; Riley, R. J. Evaluation of fresh and cryopreserved hepatocytes as in vitro drug metabolism tools for the prediction of metabolic clearance Drug Metab. Dispos. 2004, 32 (11) 1247-53 (Pubitemid 39410908)
8. Hewitt, N. J.; Lechon, M. J.; Houston, J. B.; Hallifax, D.; Brown, H. S.; Maurel, P.; Kenna, J. G.; Gustavsson, L.; Lohmann, C.; Skonberg, C.; Guillouzo, A.; Tuschl, G.; Li, A. P.; LeCluyse, E.; Groothuis, G. M.; Hengstler, J. G. Primary hepatocytes: current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies Drug Metab. Rev. 2007, 39 (1) 159-234
9. Poirier, A.; Lave, T.; Portmann, R.; Brun, M. E.; Senner, F.; Kansy, M.; Grimm, H. P.; Funk, C. Design, data analysis, and simulation of in vitro drug transport kinetic experiments using a mechanistic in vitro model Drug Metab. Dispos. 2008, 36 (12) 2434-44
10. Soars, M. G.; Grime, K.; Sproston, J. L.; Webborn, P. J.; Riley, R. J. Use of hepatocytes to assess the contribution of hepatic uptake to clearance in vivo Drug Metab. Dispos. 2007, 35 (6) 859-65 (Pubitemid 46798596)
11. Lam, J. L.; Okochi, H.; Huang, Y.; Benet, L. Z. In vitro and in vivo correlation of hepatic transporter effects on erythromycin metabolism: characterizing the importance of transporter-enzyme interplay Drug Metab. Dispos. 2006, 34 (8) 1336-44 (Pubitemid 44079874)
12. Griffin, S. J.; Houston, J. B. Prediction of in vitro intrinsic clearance from hepatocytes: comparison of suspensions and monolayer cultures Drug Metab. Dispos. 2005, 33 (1) 115-20 (Pubitemid 40023522)
13. Li, A. P.; Lu, C.; Brent, J. A.; Pham, C.; Fackett, A.; Ruegg, C. E.; Silber, P. M. Cryopreserved human hepatocytes: characterization of drug-metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug-drug interaction potential Chem. Biol. Interact. 1999, 121 (1) 17-35 (Pubitemid 29240667)
14. Sjogren, E.; Bredberg, U.; Allard, E.; Arvidsson, B.; Bergquist, J.; Andersson, T. B.; Lennernas, H. Hepatic disposition of ximelagatran and its metabolites in pig; prediction of the impact of membrane transporters through a simple disposition model Pharm. Res. 2010, 27 (4) 597-607
15. Bidstrup, T. B.; Bjornsdottir, I.; Sidelmann, U. G.; Thomsen, M. S.; Hansen, K. T. CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide Br. J. Clin. Pharmacol. 2003, 56 (3) 305-14 (Pubitemid 37059658)
16. van Heiningen, P. N.; Hatorp, V.; Kramer Nielsen, K.; Hansen, K. T.; van Lier, J. J.; De Merbel, N. C.; Oosterhuis, B.; Jonkman, J. H. Absorption, metabolism and excretion of a single oral dose of (14)C-repaglinide during repaglinide multiple dosing Eur. J. Clin. Pharmacol. 1999, 55 (7) 521-5 (Pubitemid 29446553)
17. Kikuchi, M. Modulation of insulin secretion in non-insulin-dependent diabetes mellitus by two novel oral hypoglycaemic agents, NN623 and A4166 Diabetic Med. 1996, 13 (9 Suppl. 6) S151-5
18. Kajosaari, L. I.; Laitila, J.; Neuvonen, P. J.; Backman, J. T. Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin Basic Clin. Pharmacol. Toxicol. 2005, 97 (4) 249-56 (Pubitemid 41433700)
19. Bauer, E.; Beschke, K.; Ebner, T.; Greischel, A.; Heinle, R.; Schiller-Rankewitz, H.; Prox, A.; Schmid, J.; Stangier, J.; Wachsmuth, H.; Wolfinger, H. Biotransformation of [14C] repaglinide in human, cynomolgus monkey, dog, rabbit, rat and mouse Diabetologia 1997, 40 (Suppl. 1) A326
20. Mandic, Z.; Gabelica, V. Ionization, lipophilicity and solubility properties of repaglinide J. Pharm. Biomed. Anal. 2006, 41 (3) 866-71
21. Hinton, L. K.; Thomas, J. S.; Kenworthy, K. E.; Somers, G. I.; Manchee, G.; Galetin, A.; Houston, J. B. Uptake of repaglinide in HEK293 cells expressing OATP1B1 and plated human hepatocytes Drug Metab. Rev. 2008, 40 (1 Suppl. 1) 152-153
22. Niemi, M.; Backman, J. T.; Kajosaari, L. I.; Leathart, J. B.; Neuvonen, M.; Daly, A. K.; Eichelbaum, M.; Kivisto, K. T.; Neuvonen, P. J. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics Clin. Pharmacol. Ther. 2005, 77 (6) 468-78 (Pubitemid 40824960)
23. Kajosaari, L. I.; Niemi, M.; Neuvonen, M.; Laitila, J.; Neuvonen, P. J.; Backman, J. T. Cyclosporine markedly raises the plasma concentrations of repaglinide Clin. Pharmacol. Ther. 2005, 78 (4) 388-99 (Pubitemid 41393674)
24. Kalliokoski, A.; Backman, J. T.; Kurkinen, K. J.; Neuvonen, P. J.; Niemi, M. Effects of gemfibrozil and atorvastatin on the pharmacokinetics of repaglinide in relation to SLCO1B1 polymorphism Clin. Pharmacol. Ther. 2008, 84 (4) 488-96
25. Niemi, M.; Backman, J. T.; Neuvonen, M.; Neuvonen, P. J. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide Diabetologia 2003, 46 (3) 347-51 (Pubitemid 36547589)
26. Bergman, E.; Lundahl, A.; Fridblom, P.; Hedeland, M.; Bondesson, U.; Knutson, L.; Lennernas, H. Enterohepatic disposition of rosuvastatin in pigs and the impact of concomitant dosing with cyclosporine and gemfibrozil Drug Metab. Dispos. 2009, 37 (12) 2349-58
27. Thorn, H. A.; Hedeland, M.; Bondesson, U.; Knutson, L.; Yasin, M.; Dickinson, P.; Lennernas, H. Different effects of ketoconazole on the stereoselective first-pass metabolism of R/S-verapamil in the intestine and the liver: important for the mechanistic understanding of first-pass drug-drug interactions Drug Metab. Dispos. 2009, 37 (11) 2186-96
28. Sjodin, E.; Fritsch, H.; Eriksson, U. G.; Logren, U.; Nordgren, A.; Forsell, P.; Knutson, L.; Lennernas, H. Intestinal and hepatobiliary transport of ximelagatran and its metabolites in pigs Drug Metab. Dispos. 2008, 36 (8) 1519-28
29. Schrickx, J. ABC-transporters in the pig. PhD, Universiteit Utrecht, Utrecht, 2006.
30. Upton, R. N. Organ weights and blood flows of sheep and pig for physiological pharmacokinetic modelling J. Pharmacol. Toxicol. Methods 2008, 58 (3) 198-205
31. Puccinelli, E.; Gervasi, P. G.; Longo, V. Xenobiotic metabolizing cytochrome P450 in pig, a promising animal model Curr. Drug Metab. 2011, 12 (6) 507-25
32. Achour, B.; Barber, J.; Rostami-Hodjegan, A. Cytochrome P450 Pig Liver Pie: Determination of individual cytochrome P450 isoform contents in microsomes from two pig livers using liquid chromatography in conjunction with mass spectrometry Drug Metab. Dispos. 2011, 39 (11) 2130-4
33. Goh, L. B.; Spears, K. J.; Yao, D.; Ayrton, A.; Morgan, P.; Roland Wolf, C.; Friedberg, T. Endogenous drug transporters in in vitro and in vivo models for the prediction of drug disposition in man Biochem. Pharmacol. 2002, 64 (11) 1569-78 (Pubitemid 35333418)
34. Yeo, K. R.; Rostami-Hodjegan, A.; Tucker, G. T. Abundance of cytochromes P450 in human liver: a meta-analysis Br. J. Clin. Pharmacol. 2004, 57 (5) 687-8
35. Gueorguieva, I.; Nestorov, I. A.; Murby, S.; Gisbert, S.; Collins, B.; Dickens, K.; Duffy, J.; Hussain, Z.; Rowland, M. Development of a whole body physiologically based model to characterise the pharmacokinetics of benzodiazepines. 1: Estimation of rat tissue-plasma partition ratios J. Pharmacokinet. Pharmacodyn. 2004, 31 (4) 269-98 (Pubitemid 39287337)
36. Webborn, P. J.; Parker, A. J.; Denton, R. L.; Riley, R. J. In vitro-in vivo extrapolation of hepatic clearance involving active uptake: theoretical and experimental aspects Xenobiotica 2007, 37 (10-11) 1090-109 (Pubitemid 350035538)
37. Paine, S. W.; Parker, A. J.; Gardiner, P.; Webborn, P. J.; Riley, R. J. Prediction of the pharmacokinetics of atorvastatin, cerivastatin, and indomethacin using kinetic models applied to isolated rat hepatocytes Drug Metab. Dispos. 2008, 36 (7) 1365-74 (Pubitemid 351929321)
38. Poirier, A.; Funk, C.; Scherrmann, J. M.; Lave, T. Mechanistic modeling of hepatic transport from cells to whole body: application to napsagatran and fexofenadine Mol. Pharmaceutics 2009, 6 (6) 1716-33
39. Liu, L.; Pang, K. S. The roles of transporters and enzymes in hepatic drug processing Drug Metab. Dispos. 2005, 33 (1) 1-9 (Pubitemid 40023507)
40. Watanabe, T.; Kusuhara, H.; Maeda, K.; Shitara, Y.; Sugiyama, Y. Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans J. Pharmacol. Exp. Ther. 2009, 328 (2) 652-62
41. Walsky, R. L.; Gaman, E. A.; Obach, R. S. Examination of 209 drugs for inhibition of cytochrome P450 2C8 J. Clin. Pharmacol. 2005, 45 (1) 68-78
42. Karlgren, M.; Ahlin, G.; Bergstrom, C. A.; Svensson, R.; Palm, J.; Artursson, P. In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug-Drug Interactions Pharm. Res. 2012, 29 (2) 411-26
43. Pelkonen, O.; Turpeinen, M.; Hakkola, J.; Honkakoski, P.; Hukkanen, J.; Raunio, H. Inhibition and induction of human cytochrome P450 enzymes: current status Arch. Toxicol. 2008, 82 (10) 667-715
44. Yao, M.; Dai, M.; Liu, Z.; Huang, L.; Chen, D.; Wang, Y.; Peng, D.; Wang, X.; Yuan, Z. Comparison of the substrate kinetics of pig CYP3A29 with pig liver microsomes and human CYP3A4 Biosci. Rep. 2011, 31 (3) 211-20
45. Sjogren, E.; Lennernas, H.; Andersson, T. B.; Grasjo, J.; Bredberg, U. The multiple depletion curves method provides accurate estimates of intrinsic clearance (CLint), maximum velocity of the metabolic reaction (Vmax), and Michaelis constant (Km): accuracy and robustness evaluated through experimental data and Monte Carlo simulations Drug Metab. Dispos. 2009, 37 (1) 47-58
46. Nordgren, A.; Karlsson, T.; Wiklund, L. Glutamine concentration and tissue exchange with intravenously administered alpha-ketoglutaric acid and ammonium: A dose-response study in the pig Nutrition 2002, 18 (6) 496-504 (Pubitemid 34586805)
47. Riley, R. J.; McGinnity, D. F.; Austin, R. P. A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes Drug Metab. Dispos. 2005, 33 (9) 1304-11 (Pubitemid 41196973)
48. Bayliss, M. K.; Bell, J. A.; Jenner, W. N.; Park, G. R.; Wilson, K. Utility of hepatocytes to model species differences in the metabolism of Loxtidine and to predict pharmacokinetic parameters in rat, dog and man Xenobiotica 1999, 29 (3) 253-68 (Pubitemid 29140095)
49. Reinoso, R. F.; Telfer, B. A.; Brennan, B. S.; Rowland, M. Uptake of teicoplanin by isolated rat hepatocytes: comparison with in vivo hepatic distribution Drug Metab. Dispos. 2001, 29 (4 Part 1) 453-9 (Pubitemid 32275560)
50. Uhal, B. D.; Roehrig, K. L. Effect of dietary state on hepatocyte size Biosci. Rep. 1982, 2 (12) 1003-7 (Pubitemid 13154913)
51. Vom Dahl, S.; Hallbrucker, C.; Lang, F.; Gerok, W.; Haussinger, D. Regulation of liver cell volume and proteolysis by glucagon and insulin Biochem. J. 1991, 278 (Part 3) 771-7
52. Hallifax, D.; Houston, J. B. Uptake and intracellular binding of lipophilic amine drugs by isolated rat hepatocytes and implications for prediction of in vivo metabolic clearance Drug Metab. Dispos. 2006, 34 (11) 1829-36 (Pubitemid 44771710)
53. Poulin, P.; Theil, F. P. Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution J. Pharm. Sci. 2002, 91 (1) 129-56 (Pubitemid 34074473)
54. Hannon, J. P.; Bossone, C. A.; Wade, C. E. Normal Physiological Values for Conscious Pigs Used in Biomedical-Research Lab. Anim. Sci. 1990, 40 (3) 293-8 (Pubitemid 20198131)
55. Elowsson, P.; Carlsten, J. Body composition of the 12-week-old pig studied by dissection Lab. Anim. Sci. 1997, 47 (2) 200-2
56. Plum, A.; Muller, L. K.; Jansen, J. A. The effects of selected drugs on the in vitro protein binding of repaglinide in human plasma Methods Find Exp. Clin. Pharmacol. 2000, 22 (3) 139-43 (Pubitemid 30413252)
57. Lundahl, A.; Hedeland, M.; Bondesson, U.; Lennernas, H. In vivo investigation in pigs of intestinal absorption, hepatobiliary disposition, and metabolism of the 5alpha-reductase inhibitor finasteride and the effects of coadministered ketoconazole Drug Metab. Dispos. 2011, 39 (5) 847-57
58. Jones, A. W.; Larsson, H. Distribution of diazepam and nordiazepam between plasma and whole blood and the influence of hematocrit Ther. Drug Monit. 2004, 26 (4) 380-5 (Pubitemid 38989657)
59. Ring, B. J.; Chien, J. Y.; Adkison, K. K.; Jones, H. M.; Rowland, M.; Jones, R. D.; Yates, J. W.; Ku, M. S.; Gibson, C. R.; He, H.; Vuppugalla, R.; Marathe, P.; Fischer, V.; Dutta, S.; Sinha, V. K.; Bjornsson, T.; Lave, T.; Poulin, P. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 3: Comparative assessement of prediction methods of human clearance J. Pharm. Sci. 2011, 100 (10) 4090-110
60. Poulin, P.; Jones, R. D.; Jones, H. M.; Gibson, C. R.; Rowland, M.; Chien, J. Y.; Ring, B. J.; Adkison, K. K.; Ku, M. S.; He, H.; Vuppugalla, R.; Marathe, P.; Fischer, V.; Dutta, S.; Sinha, V. K.; Bjornsson, T.; Lave, T.; Yates, J. W. PHRMA CPCDC initiative on predictive models of human pharmacokinetics, part 5: Prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling approach J. Pharm. Sci. 2011, 100 (10) 4127-57
61. Nestorov, I. Whole-body physiologically based pharmacokinetic models Expert Opin. Drug Metab. Toxicol. 2007, 3 (2) 235-49 (Pubitemid 47321518)
62. Gertz, M.; Houston, J. B.; Galetin, A. Physiologically Based Pharmacokinetic Modeling of Intestinal First-Pass Metabolism of CYP3A Substrates with High Intestinal Extraction Drug Metab. Dispos. 2011, 39 (9) 1633-42