Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide

British Journal of Clinical Pharmacology

Volumn 60, Issue 2, 2005, Pages 208-217

  Niemi, Mikko ^a,b   Backman, Janne T ^a   Juntti Patinen, Laura ^a   Neuvonen, Mikko ^a   Neuvonen, Pertti J ^a  

^a UNIVERSITY OF HELSINKI   (Finland)

^b HELSINKI UNIVERSITY CENTRAL HOSPITAL   (Finland)

Author keywords

CYP2C9; CYP3A4; Drug interaction; Gemfibrozil; Itraconazole; Nateglinide

Indexed keywords

CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; DRUG METABOLITE; GEMFIBROZIL; GLUCOSE; ITRACONAZOLE; NATEGLINIDE; PLACEBO; REPAGLINIDE;

ADULT; AREA UNDER THE CURVE; ARTICLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG EFFECT; DRUG ELIMINATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENCY; DRUG STRUCTURE; ENZYME ACTIVITY; ENZYME INHIBITION; FEMALE; GLUCOSE BLOOD LEVEL; HUMAN; HUMAN EXPERIMENT; IN VIVO STUDY; MALE; NORMAL HUMAN; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL;

ADMINISTRATION, ORAL; ADULT; ANTIFUNGAL AGENTS; ANTILIPEMIC AGENTS; AREA UNDER CURVE; ARYL HYDROCARBON HYDROXYLASES; BLOOD GLUCOSE; CROSS-OVER STUDIES; CYCLOHEXANES; CYTOCHROME P-450 ENZYME SYSTEM; DRUG INTERACTIONS; FEMALE; GEMFIBROZIL; HUMANS; HYPOGLYCEMIC AGENTS; ITRACONAZOLE; MALE; PHENYLALANINE;

EID: 23044456599     PISSN: 03065251     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1365-2125.2005.02385.x     Document Type: Article

References (55)

1. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 2003; 46: 347-51.
2. van Heiningen PN, Hatorp V, Kramer Nielsen K, Hansen KT, van Lier JJ, De Merbel NC, Oosterhuis B, Jonkman JH. Absorption, metabolism and excretion of a single oral dose of (14) C-repaglinide during repaglinide multiple dosing. Eur J Clin Pharmacol 1999; 55: 521-5.
3. Bidstrup TB, Bjørnsdottir I, Sidelmann UG, Thomsen MS, Hansen KT. 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: 305-14.
4. Wang JS, Neuvonen M, Wen X, Backman JT, Neuvonen PJ. Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos 2002; 30: 1352-6.
5. Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 2002; 72: 685-91.
6. Backman JT, Kyrklund C, Kivistö KT, Wang JS, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther 2000; 68: 122-9.
7. Jurima-Romet M, Crawford K, Cyr T, Inaba T. Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals. Drug Metab Dispos 1994; 22: 849-57.
8. Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 55: 481-5.
9. Ong CE, Coulter S, Birkett DJ, Bhasker CR, Miners JO. The xenobiotic inhibitor profile of cytochrome P4502C8. Br J Clin Pharmacol 2000; 50: 573-80.
10. Wen X, Wang JS, Backman JT, Kivistö KT, Neuvonen PJ. Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab Dispos 2001; 29: 1359-61.
11. McLeod JF. Clinical pharmacokinetics of nateglinide: a rapidly-absorbed, short-acting insulinotropic agent. Clin Pharmacokinet 2004; 43: 97-120.
12. Weaver ML, Orwig BA, Rodriguez LC, Graham ED, Chin JA, Shapino MJ, McLeod JF, Mangold JB. Pharmacokinetics and metabolism of nateglinide in humans. Drug Metab Dispos 2001; 29: 415-21.
13. Hatorp V. Clinical pharmacokinetics and pharmacodynamics of repaglinide. Clin Pharmacokinet 2002; 41: 471-83.
14. Takesada H, Matsuda K, Ohtake R, Mihara R, Ono I, Tanaka K, Naito M, Yatagai M, Suzuki E. Structure determination of metabolites isolated from urine and bile after administration of AY4166, a novel D-phenylalanine-derivative hypoglycemic agent. Bioorg Med Chem 1996; 4: 1771-81.
15. Back DJ, Tjia JF, Karbwang J, Colbert J. In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines. Br J Clin Pharmacol 1988; 26: 23-9.
16. Niemi M, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ, Kivistö KT. Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Clin Pharmacol Ther 2001; 69: 194-200.
17. Wienkers LC, Wurden G, Storch E, Kunze KL, Rettie AE, Trager WF. Formation of (R)-8-hydroxywarfarin in human liver microsomes. A new metabolic marker for the (S)-mephenytoin hydroxylase, P4502C19. Drug Metab Dispos 1996; 24: 610-4.
18. Back DJ, Tjia JF. Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes. Br J Clin Pharmacol 1991; 32: 624-6.
19. Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996; 82: 511-6.
20. Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet 2000; 38: 111-80.
21. Niemi M, Neuvonen M, Juntti-Patinen L, Backman JT, Neuvonen PJ. Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide. Clin Pharmacol Ther 2003; 74: 25-31.
22. Hengy H, Kölle EU. Determination of gemfibrozil in plasma by high performance liquid chromatography. Arzneimittelforschung 1985; 35: 1637-9.
23. Remmel RP, Dombrovskis D, Canafax DM. Assay of itraconazole in leukemic patient plasma by reversed-phase small-bore liquid chromatography. J Chromatogr 1988; 432: 388-94.
24. Allenmark S, Edebo A, Lindgren K. Determination of itraconazole in serum with high-performance liquid chromatography and fluorescence detection. J Chromatogr 1990; 532: 203-6.
25. Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications, 3rd edn. Baltimore: Williams & Wilkins, 1995.
26. Kirchheiner J, Meineke I, Muller G, Bauer S, Rohde W, Meisel C, Roots I, Brockmöller J. Influence of CYP2C9 and CYP2D6 polymorphisms on the pharmacokinetics of nateglinide in genotyped healthy volunteers. Clin Pharmacokinet 2004; 43: 267-78.
27. Kivistö KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998; 46: 49-53.
28. Niemi M, Backman JT, Granfors M, Laitila J, Neuvonen M, Neuvonen PJ. Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. Diabetologia 2003; 46: 1319-23.
29. Niemi M, Cascorbi I, Timm R, Kroemer HK, Neuvonen PJ, Kivistö KT. Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin Pharmacol Ther 2002; 72: 326-32.
30. Niemi M, Neuvonen PJ, Kivistö KT. Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of glimepiride. Clin Pharmacol Ther 2001; 70: 439-45.
31. Lilja JJ, Backman JT, Neuvonen PJ. Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects. Br J Clin Pharmacol 2004; doi: 10.1111/j.1365-2125.2004.02323.
32. Shitara Y, Hirano M, Sato H, Sugiyama Y. Gemfibrozil and its glucuronide inhibit the OATP2 (OATP1B1: SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin. J Pharmacol Exp Ther 2004; 311: 228-36.
33. Sabordo L, Sallustio BC, Evans AM, Nation RL. Hepatic disposition of the acyl glucuronide 1-O-gemfibrozil-beta-D-glucuronide: effects of clofibric acid, acetaminophen, and acetaminophen glucuronide. J Pharmacol Exp Ther 2000; 295: 44-50.
34. Sabordo L, Sallustio BC, Evans AM, Nation RL. Hepatic disposition of the acyl glucuronide 1-O-gemfibrozil-beta-D-glucuronide: effects of dibromosulfophthalein on membrane transport and aglycone formation. J Pharmacol Exp Ther 1999; 288: 414-20.
35. Sallustio BC, Fairchild BA, Shanahan K, Evans AM, Nation RL. Disposition of gemfibrozil and gemfibrozil acyl glucuronide in the rat isolated perfused liver. Drug Metab Dispos 1996; 24: 984-9.
36. Schoch GA, Yano JK, Wester MR, Griffin KJ, Stout CD, Johnson EF. Structure of human microsomal cytochrome P450 2C8. Evidence for a peripheral fatty acid binding site. J Biol Chem 2004; 279: 9497-503.
37. Williams PA, Cosme J, Ward A, Angove HC, Matak Vinkovic D, Jhoti H. Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature 2003; 424: 464-8.
38. Ohyama K, Nakajima M, Nakamura S, Shimada N, Yamazaki H, Yokoi T. A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation: an approach to predict the contribution with relative activity factor. Drug Metab Dispos 2000; 28: 1303-10.
39. Li XQ, Björkman A, Andersson TB, Ridderström M, Masimirembwa CM. Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J Pharmacol Exp Ther 2002; 300: 399-407.
40. Sonnichsen DS, Liu Q, Schuetz EG, Schuetz JD, Pappo A, Relling MV. Variability in human cytochrome P450 paclitaxel metabolism. J Pharmacol Exp Ther 1995; 275: 566-75.
41. Prueksaritanont T, Ma B, Yu N. The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6. Br J Clin Pharmacol 2003; 56: 120-4.
42. Busse D, Cosme J, Beaune P, Kroemer HK, Eichelbaum M. Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol 1995; 353: 116-21.
43. Kumar S, Samuel K, Subramanian R, Braun MP, Steams RA, Chiu SH, Evans DC, Baillie TA. Extrapolation of diclofenac clearance from in vitro microsomal metabolism data: role of acyl glucuronidation and sequential oxidative metabolism of the acyl glucuronide. J Pharmacol Exp Ther 2002; 303: 969-78.
44. Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW. Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother 2002; 46: 160-5.
45. Jalava KM, Partanen J, Neuvonen PJ. Itraconazole decreases renal clearance of digoxin. Ther Drug Monit 1997; 19: 609-13.
46. Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch 2004; 447: 653-65.
47. Fromm MF. Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol Sci 2004; 25: 423-9.
48. Terada T, Sawada K, Saito H, Hashimoto Y, Inui K. Inhibitory effect of novel oral hypoglycemic agent nateglinide (AY4166) on peptide transporters PEPT1 and PEPT2. Eur J Pharmacol 2000; 392: 11-7.
49. Okamura A, Emoto A, Koyabu N, Ohtani H, Sawada Y. Transport and uptake of nateglinide in Caco-2 cells and its inhibitory effect on human monocarboxylate transporter MCT1. Br J Pharmacol 2002; 137: 391-9.
50. Miller DB, Spence JD. Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet 1998; 34: 155-62.
51. Schäfer-Korting M, Korting HC, Amann F, Peuser R, Lukacs A. Influence of albumin on itraconazole and ketoconazole antifungal activity: results of a dynamic in vitro study. Antimicrob Agents Chemother 1991; 35: 2053-6.
52. Wooltorton E. Repaglinide and gemfibrozil interaction: serious hypoglycemia. CMAJ 2003; 169: 813.
53. EMEA public statement on repaglinide (Novonorm/Prandin): Contraindication of Concomitant Use of Repaglinide and Gemfibrozil [Online;. London 21 May 2003. Available from URL http://www.emea.eu.int/htms/human/drugalert/drugalert.htm
54. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects. Br J Clin Pharmacol 2003; 56: 427-32.
55. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, Kivistö KT. Rifampin decreases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther 2000; 68: 495-500.