Autoinhibition of CYP3A4 leads to important role of CYP2C8 in imatinib metabolism: Variability in CYP2C8 activity may alter plasma concentrations and response

Drug Metabolism and Disposition

Volumn 41, Issue 1, 2013, Pages 50-59

  Filppula, Anne M ^a   Neuvonen, Mikko ^a   Laitila, Jouko ^a   Neuvonen, Pertti J ^a,b   Backman, Janne T ^a,b  

^a UNIVERSITY OF HELSINKI   (Finland)

^b HELSINKI UNIVERSITY CENTRAL HOSPITAL   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450 2C8; CYTOCHROME P450 3A4; CYTOCHROME P450 INHIBITOR; GEMFIBROZIL; IMATINIB;

ADULT; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG ELIMINATION; DRUG METABOLISM; DRUG POTENTIATION; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; HUMAN CELL; IN VITRO STUDY; INHIBITION KINETICS; LIVER CLEARANCE; LIVER MICROSOME; MALE; PRIORITY JOURNAL; PROCESS MODEL; PROTEIN DEPLETION; PROTEIN FUNCTION; QUANTITATIVE ANALYSIS; SINGLE DRUG DOSE; STEADY STATE;

ANTINEOPLASTIC AGENTS; ARYL HYDROCARBON HYDROXYLASES; BENZAMIDES; CYTOCHROME P-450 CYP3A; HUMANS; MICROSOMES, LIVER; PIPERAZINES; PYRIMIDINES; RECOMBINANT PROTEINS;

EID: 84871540169     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.112.048017     Document Type: Article

References (53)

1. Apperley JF (2007) Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 8:1018-1029.
2. Aquilante CL, Kosmiski LA, and Bourne DW, et al. (2012) Impact of the CYP2C8*3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone. Br J Clin Pharmacol [published ahead of print].
3. Backman JT, Kyrklund C, Neuvonen M, and Neuvonen PJ (2002) Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 72:685-691. (Pubitemid 36021007)
4. Baldwin SJ, Bloomer JC, Smith GJ, Ayrton AD, Clarke SE, and Chenery RJ (1995) Ketoconazole and sulphaphenazole as the respective selective inhibitors of P4503A and 2C9. Xenobiotica 25:261-270.
5. Bolton AE, Peng B, Hubert M, Krebs-Brown A, Capdeville R, Keller U, and Seiberling M (2004) Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol 53:102-106. (Pubitemid 38186987)
6. Bornhäuser M, Pursche S, Bonin M, Freiberg-Richter J, Jenke A, Illmer T, Ehninger G, and Schleyer E (2005) Elimination of imatinib mesylate and its metabolite N-desmethyl-imatinib. J Clin Oncol 23:3855-3856, author reply 3857-3858.
7. Bourrié M, Meunier V, Berger Y, and Fabre G (1996) Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions catalyzed by human liver microsomes. J Pharmacol Exp Ther 277:321-332. (Pubitemid 27169077)
8. Davies B and Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093-1095. (Pubitemid 23211439)
9. Demetri GD, Wang Y, Wehrle E, Racine A, Nikolova Z, Blanke CD, Joensuu H, and von Mehren M (2009) Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 27:3141-3147.
10. Draper AJ, Madan A, and Parkinson A (1997) Inhibition of coumarin 7-hydroxylase activity in human liver microsomes. Arch Biochem Biophys 341:47-61. (Pubitemid 27198030)
11. Duffaud F and Le Cesne A (2009) Imatinib in the treatment of solid tumours. Target Oncol 4:45-56.
12. Dutreix C, Peng B, Mehring G, Hayes M, Capdeville R, Pokorny R, and Seiberling M (2004) Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects. Cancer Chemother Pharmacol 54:290-294. (Pubitemid 39304422)
13. Eagling VA, Tjia JF, and Back DJ (1998) Differential selectivity of cytochrome P450 inhibitors against probe substrates in human and rat liver microsomes. Br J Clin Pharmacol 45:107-114. (Pubitemid 28045676)
14. Eechoute K, Sparreboom A, Burger H, Franke RM, Schiavon G, Verweij J, Loos WJ, Wiemer EA, and Mathijssen RH (2011) Drug transporters and imatinib treatment: implications for clinical practice. Clin Cancer Res 17:406-415.
15. Filppula AM, Laitila J, Neuvonen PJ, and Backman JT (2012) Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol 165:2787-2798.
16. Gibbons J, Egorin MJ, and Ramanathan RK, et al.; National Cancer Institute Organ Dysfunction Working Group (2008) Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 26:570-576. (Pubitemid 351264350)
17. Gschwind HP, Pfaar U, and Waldmeier F, et al. (2005) Metabolism and disposition of imatinib mesylate in healthy volunteers. Drug Metab Dispos 33:1503-1512. (Pubitemid 41323999)
18. Honkalammi J, Niemi M, Neuvonen PJ, and Backman JT (2012) Gemfibrozil is a strong inactivator of CYP2C8 in very small multiple doses. Clin Pharmacol Ther 91:846-855.
19. Houston JB and Galetin A (2008) Methods for predicting in vivo pharmacokinetics using data from in vitro assays. Curr Drug Metab 9:940-951.
20. Howgate EM, Rowland Yeo K, Proctor NJ, Tucker GT, and Rostami-Hodjegan A (2006) Prediction of in vivo drug clearance from in vitro data. I: impact of inter-individual variability. Xenobiotica 36:473-497. (Pubitemid 43890728)
21. Jamei M, Dickinson GL, and Rostami-Hodjegan A (2009) A framework for assessing interindividual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: A tale of 'bottom-up' vs ' top-down' recognition of covariates. Drug Metab Pharmacokinet 24:53-75.
22. Kim DW, Tan EY, Jin Y, Park S, Hayes M, Demirhan E, Schran H, and Wang Y (2011) Effects of imatinib mesylate on the pharmacokinetics of paracetamol (acetaminophen) in Korean patients with chronic myelogenous leukaemia. Br J Clin Pharmacol 71:199-206.
23. Kirchheiner J, Thomas S, and Bauer S, et al. (2006) Pharmacokinetics and pharmacodynamics of rosiglitazone in relation to CYP2C8 genotype. Clin Pharmacol Ther 80:657-667. (Pubitemid 44920222)
24. Ko JW, Sukhova N, Thacker D, Chen P, and Flockhart DA (1997) Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. Drug Metab Dispos 25:853-862. (Pubitemid 27318604)
25. Koenigs LL, Peter RM, Thompson SJ, Rettie AE, and Trager WF (1997) Mechanism-based inactivation of human liver cytochrome P450 2A6 by 8-methoxypsoralen. Drug Metab Dispos 25:1407-1415. (Pubitemid 28010927)
26. Kovacsovics T and Maziarz RT (2006) Philadelphia chromosome-positive acute lymphoblastic leukemia: impact of imatinib treatment on remission induction and allogeneic stem cell transplantation. Curr Oncol Rep 8:343-351. (Pubitemid 44336297)
27. Larson RA, Druker BJ, Guilhot F, O'Brien SG, Riviere GJ, Krahnke T, Gathmann I, and Wang Y; IRIS (International Randomized Interferon vs STI571) Study Group (2008) Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111:4022-4028.
28. Lin JH and Lu AY (1998) Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 35:361-390. (Pubitemid 28520008)
29. Marull M and Rochat B (2006) Fragmentation study of imatinib and characterization of new imatinib metabolites by liquid chromatography-triple- quadrupole and linear ion trap mass spectrometers. J Mass Spectrom 41:390-404.
30. Nebot N, Crettol S, d'Esposito F, Tattam B, Hibbs DE, and Murray M (2010) Participation of CYP2C8 and CYP3A4 in the N-demethylation of imatinib in human hepatic microsomes. Br J Pharmacol 161:1059-1069.
31. Newton DJ, Wang RW, and Lu AY (1995) Cytochrome P450 inhibitors. Evaluation of specificities in the in vitrometabolism of therapeutic agents by human liver microsomes. Drug Metab Dispos 23:154-158.
32. Nikolova Z, Peng B, Hubert M, Sieberling M, Keller U, Ho YY, Schran H, and Capdeville R (2004) Bioequivalence, safety, and tolerability of imatinib tablets compared with capsules. Cancer Chemother Pharmacol 53:433-438. (Pubitemid 38553666)
33. Ogilvie BW, Zhang D, Li W, Rodrigues AD, Gipson AE, Holsapple J, Toren P, and Parkinson A (2006) Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug Metab Dispos 34:191-197. (Pubitemid 43042661)
34. Olkkola KT, Backman JT, and Neuvonen PJ (1994) Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 55:481-485. (Pubitemid 24192233)
35. Peng B, Dutreix C, Mehring G, Hayes MJ, Ben-Am M, Seiberling M, Pokorny R, Capdeville R, and Lloyd P (2004a) Absolute bioavailability of imatinib (Glivec) orally versus intravenous infusion. J Clin Pharmacol 44:158-162. (Pubitemid 38114314)
36. Peng B, Hayes M, and Resta D, et al. (2004b) Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 22:935-942. (Pubitemid 41103606)
37. Peng B, Lloyd P, and Schran H (2005) Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 44:879-894. (Pubitemid 41252840)
38. Peters SA, Schroeder PE, Giri N, and Dolgos H (2012) Evaluation of the use of static and dynamic models to predict drug-drug interaction and its associated variability: impact on drug discovery and early development. Drug Metab Dispos 40:1495-1507.
39. Picard S, Titier K, and Etienne G, et al. (2007) Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 109:3496-3499. (Pubitemid 46572540)
40. Proctor NJ, Tucker GT, and Rostami-Hodjegan A (2004) Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica 34:151-178. (Pubitemid 38299716)
41. Richter T, Mürdter TE, Heinkele G, Pleiss J, Tatzel S, Schwab M, Eichelbaum M, and Zanger UM (2004) Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J Pharmacol Exp Ther 308:189-197. (Pubitemid 38090717)
42. Rochat B, Zoete V, Grosdidier A, von Grünigen S, Marull M, and Michielin O (2008) In vitro biotransformation of imatinib by the tumor expressed CYP1A1 and CYP1B1. Biopharm Drug Dispos 29:103-118. (Pubitemid 351516391)
43. Rostami-Hodjegan A and Tucker GT (2007) Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Discov 6:140-148. (Pubitemid 46745341)
44. Rowland Yeo K, Jamei M, Yang J, Tucker GT, and Rostami-Hodjegan A (2010) Physiologically based mechanistic modelling to predict complex drug-drug interactions involving simultaneous competitive and time-dependent enzyme inhibition by parent compound and its metabolite in both liver and gut - the effect of diltiazem on the time-course of exposure to triazolam. Eur J Pharm Sci 39:298-309.
45. Rowland Yeo K, Walsky RL, Jamei M, Rostami-Hodjegan A, and Tucker GT (2011) Prediction of time-dependent CYP3A4 drug-drug interactions by physiologically based pharmacokinetic modelling: impact of inactivation parameters and enzyme turnover. Eur J Pharm Sci 43:160-173.
46. Stegmeier F, Warmuth M, Sellers WR, and Dorsch M (2010) Targeted cancer therapies in the twenty-first century: lessons from imatinib. Clin Pharmacol Ther 87:543-552.
47. Takahashi N, Wakita H, and Miura M, et al. (2010) Correlation between imatinib pharmacokinetics and clinical response in Japanese patients with chronic-phase chronic myeloid leukemia. Clin Pharmacol Ther 88:809-813.
48. Teng JF, Mabasa VH, and Ensom MH (2012) The role of therapeutic drug monitoring of imatinib in patients with chronic myeloid leukemia and metastatic or unresectable gastrointestinal stromal tumors. Ther Drug Monit 34:85-97.
49. Tornio A, Niemi M, Neuvonen PJ, and Backman JT (2008) Trimethoprim and the CYP2C8*3 allele have opposite effects on the pharmacokinetics of pioglitazone. Drug Metab Dispos 36:73-80.
50. van Erp NP, Gelderblom H, Karlsson MO, Li J, Zhao M, Ouwerkerk J, Nortier JW, Guchelaar HJ, Baker SD, and Sparreboom A (2007) Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. Clin Cancer Res 13:7394-7400.
51. Venkatakrishnan K, von Moltke LL, Obach RS, and Greenblatt DJ (2003) Drug metabolism and drug interactions: application and clinical value of in vitro models. Curr Drug Metab 4:423-459. (Pubitemid 37279366)
52. Walsky RL, Obach RS, Gaman EA, Gleeson JP, and Proctor WR (2005) Selective inhibition of human cytochrome P4502C8 by montelukast. Drug Metab Dispos 33:413-418. (Pubitemid 40279942)
53. Wang J, Hughes TP, Kok CH, Saunders VA, Frede A, Groot-Obbink K, Osborn M, Somogyi AA, D'Andrea RJ, and White DL (2012) Contrasting effects of diclofenac and ibuprofen on active imatinib uptake into leukaemic cells. Br J Cancer 106:1772-1778.