Drug interactions with oral antidiabetic agents: Pharmacokinetic mechanisms and clinical implications

Trends in Pharmacological Sciences

Volumn 33, Issue 6, 2012, Pages 312-322

  Tornio, Aleksi ^a   Niemi, Mikko ^a   Neuvonen, Pertti J ^a   Backman, Janne T ^a  

^a UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; DIPEPTIDYL PEPTIDASE IV INHIBITOR; FLUCONAZOLE; GEMFIBROZIL; GLIBENCLAMIDE; GLICLAZIDE; GLIMEPIRIDE; GLIPIZIDE; GLITAZONE DERIVATIVE; GLYCOPROTEIN P; ITRACONAZOLE; LINAGLIPTIN; MEGLITINIDE; METFORMIN; NATEGLINIDE; ORAL ANTIDIABETIC AGENT; PIOGLITAZONE; PYRIMETHAMINE; REPAGLINIDE; RIFAMPICIN; ROSIGLITAZONE; SAXAGLIPTIN; SITAGLIPTIN; SULFINPYRAZONE; SULFONYLUREA DERIVATIVE; UNINDEXED DRUG; VERAPAMIL; VILDAGLIPTIN;

AREA UNDER THE CURVE; DOSE TIME EFFECT RELATION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG CONTRAINDICATION; DRUG EFFECT; DRUG ELIMINATION; DRUG EXCRETION; DRUG HALF LIFE; DRUG INTERACTION; DRUG MECHANISM; DRUG MEGADOSE; DRUG METABOLISM; DRUG POTENTIATION; DRUG PROTEIN BINDING; DRUG UPTAKE; ENZYME INHIBITION; FLUID RETENTION; FOOD; FOOD DRUG INTERACTION; GASTROINTESTINAL SYMPTOM; HUMAN; HYPOGLYCEMIA; INTESTINE ABSORPTION; KIDNEY CLEARANCE; LACTIC ACIDOSIS; LOW DRUG DOSE; MAXIMUM PLASMA CONCENTRATION; NON INSULIN DEPENDENT DIABETES MELLITUS; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; SINGLE DRUG DOSE;

ADMINISTRATION, ORAL; ARYL HYDROCARBON HYDROXYLASES; BENZAMIDES; CYTOCHROME P-450 ENZYME SYSTEM; DIABETES MELLITUS, TYPE 2; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DRUG INTERACTIONS; HUMANS; HYPOGLYCEMIA; HYPOGLYCEMIC AGENTS; METFORMIN; SULFONYLUREA COMPOUNDS; THIAZOLIDINEDIONES;

EID: 84861873012     PISSN: 01656147     EISSN: 18733735     Source Type: Journal    
DOI: 10.1016/j.tips.2012.03.001     Document Type: Review

References (105)

1. Whiting, D.R. et al. (2011) IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res. Clin. Pract. 94, 311-321
2. Gaede, P. et al. (2008) Effect of a multifactorial intervention on mortality in type 2 diabetes. N. Engl. J. Med. 358, 580-591 (Pubitemid 351214285)
3. Caughey, G.E. et al. (2010) Comorbidity in the elderly with diabetes: identification of areas of potential treatment conflicts. Diabetes Res. Clin. Pract. 87, 385-393
4. Girardin, E. et al. (1992) [Hypoglycemia induced by oral hypoglycemic agents. Records of the French Regional Pharmacovigilance Centers 1985-1990]. Ann. Med. Interne (Paris) 143, 11-17
5. Self, T.H. et al. (1989) Interaction of rifampin and glyburide. Chest 96, 1443-1444 (Pubitemid 20000868)
6. Giacomini, K.M. et al. (2010) Membrane transporters in drug development. Nat. Rev. Drug Discov. 9, 215-236
7. Yang, J. et al. (2008) Cytochrome p450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions. Curr. Drug Metab. 9, 384-394
8. Niemi, M. et al. (2003) Pharmacokinetic interactions with rifampicin: clinical relevance. Clin. Pharmacokinet. 42, 819-850 (Pubitemid 36995083)
9. Phielix, E. et al. (2011) The role of metformin and thiazolidinediones in the regulation of hepatic glucose metabolism and its clinical impact. Trends Pharmacol. Sci. 32, 607-616
10. Graham, G.G. et al. (2011) Clinical pharmacokinetics of metformin. Clin. Pharmacokinet. 50, 81-98
11. Pentikäinen, P.J. et al. (1979) Pharmacokinetics of metformin after intravenous and oral administration to man. Eur. J. Clin. Pharmacol. 16, 195-202 (Pubitemid 10227380)
12. Zolk, O. (2012) Disposition of metformin: variability due to polymorphisms of organic cation transporters. Ann. Med. 44, 119-129
13. Kusuhara, H. et al. (2011) Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects. Clin. Pharmacol. Ther. 89, 837-844
14. Somogyi, A. et al. (1987) Reduction of metformin renal tubular secretion by cimetidine in man. Br. J. Clin. Pharmacol. 23, 545-551 (Pubitemid 17087957)
15. Tsuda, M. et al. (2009) Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J. Pharmacol. Exp. Ther. 329, 185-191
16. Cho, S.K. et al. (2011) Rifampin enhances the glucose-lowering effect of metformin and increases OCT1 mRNA levels in healthy participants. Clin. Pharmacol. Ther. 89, 416-421
17. Fahrmayr, C. et al. (2010) Hepatic OATP and OCT uptake transporters: their role for drug-drug interactions and pharmacogenetic aspects. Drug Metab. Rev. 42, 380-401
18. Neuvonen, P.J. and Kivistö, K.T. (1991) The effects of magnesium hydroxide on the absorption and efficacy of two glibenclamide preparations. Br. J. Clin. Pharmacol. 32, 215-220
19. Neuvonen, P.J. and Kivistö, K.T. (1994) Enhancement of drug absorption by antacids. An unrecognised drug interaction. Clin. Pharmacokinet. 27, 120-128 (Pubitemid 24244852)
20. Holstein, A. and Beil, W. (2009) Oral antidiabetic drug metabolism: pharmacogenomics and drug interactions. Expert Opin. Drug Metab. Toxicol. 5, 225-241
21. Kirchheiner, J. et al. (2005) Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin. Pharmacokinet. 44, 1209-1225 (Pubitemid 41832564)
22. Zhou, L. et al. (2010) Contributions of human cytochrome P450 enzymes to glyburide metabolism. Biopharm. Drug Dispos. 31, 228-242
23. Naritomi, Y. et al. (2004) Identification and relative contributions of human cytochrome P450 isoforms involved in the metabolism of glibenclamide and lansoprazole: evaluation of an approach based on the in vitro substrate disappearance rate. Xenobiotica 34, 415-427 (Pubitemid 38901452)
24. Zharikova, O.L. et al. (2009) Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide. Biochem. Pharmacol. 78, 1483-1490
25. Kirchheiner, J. et al. (2002) Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin. Pharmacol. Ther. 71, 286-296 (Pubitemid 34311458)
26. Niemi, M. et al. (2002) Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin. Pharmacol. Ther. 72, 326-332
27. Xu, H. et al. (2009) Influence of genetic polymorphisms on the pharmacokinetics and pharmaco-dynamics of sulfonylurea drugs. Curr. Drug Metab. 10, 643-658
28. Baxter, K. (ed.) (2005) Stockley's Drug Interactions (7th edn), Pharmaceutical Press
29. Fleishaker, J.C. and Phillips, J.P. (1991) Evaluation of a potential interaction between erythromycin and glyburide in diabetic volunteers. J. Clin. Pharmacol. 31, 259-262
30. Sjöberg, S. et al. (1987) Lack of pharmacokinetic interaction between glibenclamide and trimethoprim-sulphamethoxazole. Diabet. Med. 4, 245-247 (Pubitemid 17075918)
31. Semple, C.G. et al. (1986) Effect of oral verapamil on glibenclamide stimulated insulin secretion. Br. J. Clin. Pharmacol. 22, 187-190 (Pubitemid 17174117)
32. Lilja, J.J. et al. (2007) Effects of clarithromycin and grapefruit juice on the pharmacokinetics of glibenclamide. Br. J. Clin. Pharmacol. 63, 732-740 (Pubitemid 46753573)
33. Kalliokoski, A. and Niemi, M. (2009) Impact of OATP transporters on pharmacokinetics. Br. J. Pharmacol. 158, 693-705
34. Niemi, M. et al. (2001) Effects of rifampin on the pharmacokinetics and pharmacodynamics of glyburide and glipizide. Clin. Pharmacol. Ther. 69, 400-406 (Pubitemid 32554545)
35. Zheng, H.X. et al. (2009) Elucidating rifampin's inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite. Clin. Pharmacol. Ther. 85, 78-85
36. Elliot, D.J. et al. (2007) Identification of the human cytochromes P450 catalysing the rate-limiting pathways of gliclazide elimination. Br. J. Clin. Pharmacol. 64, 450-457 (Pubitemid 47404317)
37. Shao, H. et al. (2010) Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. J. Clin. Pharm. Ther. 35, 351-360
38. Zhou, K. et al. (2010) Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: a Go-DARTS study. Clin. Pharmacol. Ther. 87, 52-56
39. Niemi, M. et al. (2001) Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Clin. Pharmacol. Ther. 69, 194-200 (Pubitemid 32382501)
40. Niemi, M. et al. (2001) Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of glimepiride. Clin. Pharmacol. Ther. 70, 439-445 (Pubitemid 33135323)
41. Kidd, R.S. et al. (1999) Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics 9, 71-80 (Pubitemid 29176726)
42. Bae, J.W. et al. (2007) Effects of CYP2C9 genetic polymorphism on the pharmacokinetics and pharmacodynamics of glipizide in healthy Korean subjects. FASEB J. 21, lb362
43. Tan, B. et al. (2010) The effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of glipizide in Chinese subjects. Eur. J. Clin. Pharmacol. 66, 145-151
44. Schelleman, H. et al. (2010) Anti-infectives and the risk of severe hypoglycemia in users of glipizide or glyburide. Clin. Pharmacol. Ther. 88, 214-222
45. Tirkkonen, T. et al. (2010) Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide. J. Intern. Med. 268, 359-366
46. Niemi, M. et al. (2000) Effect of rifampicin on the pharmacokinetics and pharmacodynamics of glimepiride. Br. J. Clin. Pharmacol. 50, 591-595 (Pubitemid 32010019)
47. Park, J.Y. et al. (2003) Effect of rifampin on the pharmacokinetics and pharmacodynamics of gliclazide. Clin. Pharmacol. Ther. 74, 334-340
48. McLeod, J.F. (2004) Clinical pharmacokinetics of nateglinide: a rapidly-absorbed, short-acting insulinotropic agent. Clin. Pharmacokinet. 43, 97-120
49. Hatorp, V. (2002) Clinical pharmacokinetics and pharmacodynamics of repaglinide. Clin. Pharmacokinet. 41, 471-483
50. Kirchheiner, J. et al. (2004) Influence of CYP2C9 and CYP2D6 polymorphisms on the pharmacokinetics of nateglinide in genotyped healthy volunteers. Clin. Pharmacokinet. 43, 267-278 (Pubitemid 38429306)
51. Niemi, M. et al. (2003) Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide. Clin. Pharmacol. Ther. 74, 25-31 (Pubitemid 36776173)
52. Sabia, H. et al. (2004) Effect of a selective CYP2C9 inhibitor on the pharmacokinetics of nateglinide in healthy subjects. Eur. J. Clin. Pharmacol. 60, 407-412 (Pubitemid 39214894)
53. Niemi, M. et al. (2005) Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide. Br. J. Clin. Pharmacol. 60, 208-217 (Pubitemid 41075907)
54. Niemi, M. et al. (2003) Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects. Br. J. Clin. Pharmacol. 56, 427-432 (Pubitemid 37188138)
55. Scheen, A.J. (2007) Drug-drug and food-drug pharmacokinetic interactions with new insulinotropic agents repaglinide and nateglinide. Clin. Pharmacokinet. 46, 93-108
56. Takanohashi, T. et al. (2010) Inhibition of human liver microsomal CYP by nateglinide. J. Pharm. Pharmacol. 62, 592-597
57. Kalliokoski, A. et al. (2010) SLCO1B1 polymorphism and oral antidiabetic drugs. Basic Clin. Pharmacol. Toxicol. 107, 775-781
58. Kajosaari, L.I. et al. (2005) Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin. Pharmacol. Toxicol. 97, 249-256 (Pubitemid 41433700)
59. Kajosaari, L.I. et al. (2005) Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin. Pharmacol. Ther. 78, 388-399 (Pubitemid 41393674)
60. Bidstrup, T.B. et al. (2003) CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br. J. Clin. Pharmacol. 56, 305-314 (Pubitemid 37059658)
61. Gan, J. et al. (2010) Repaglinide-gemfibrozil drug interaction: inhibition of repaglinide glucuronidation as a potential additional contributing mechanism. Br. J. Clin. Pharmacol. 70, 870-880
62. Niemi, M. et al. (2005) Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin. Pharmacol. Ther. 77, 468-478 (Pubitemid 40824960)
63. Niemi, M. et al. (2011) Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol. Rev. 63, 157-181
64. Niemi, M. et al. (2003) Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 46, 347-351 (Pubitemid 36547589)
65. Ogilvie, B.W. et al. (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)
66. Shitara, Y. et al. (2004) Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1: SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J. Pharmacol. Exp. Ther. 311, 228-236 (Pubitemid 39287802)
67. Tornio, A. et al. (2008) The effect of gemfibrozil on repaglinide pharmacokinetics persists for at least 12 h after the dose: evidence for mechanism-based inhibition of CYP2C8 in vivo. Clin. Pharmacol. Ther. 84, 403-411
68. Backman, J.T. et al. (2009) CYP2C8 activity recovers within 96 hours after gemfibrozil dosing: estimation of CYP2C8 half-life using repaglinide as an in vivo probe. Drug Metab. Dispos. 37, 2359-2366
69. Honkalammi, J. et al. (2011) Dose-dependent interaction between gemfibrozil and repaglinide in humans: strong inhibition of CYP2C8 with subtherapeutic gemfibrozil doses. Drug Metab. Dispos. 39, 1977-1986
70. Honkalammi, J. et al. (2012) Gemfibrozil is a strong inactivator of CYP2C8 in very small multiple doses. Clin. Pharmacol. Ther. DOI: 10.1038/clpt.2011.313
71. Honkalammi, J. et al. (2011) Mechanism-based inactivation of CYP2C8 by gemfibrozil occurs rapidly in humans. Clin. Pharmacol. Ther. 89, 579-586
72. Niemi, M. et al. (2004) The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects. Br. J. Clin. Pharmacol. 57, 441-447 (Pubitemid 38519649)
73. Hatorp, V. et al. (2003) Influence of drugs interacting with CYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of the prandial glucose regulator repaglinide. J. Clin. Pharmacol. 43, 649-660 (Pubitemid 36613124)
74. Kajosaari, L.I. et al. (2006) Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide. Clin. Pharmacol. Ther. 79, 231-242
75. Niemi, M. et al. (2001) The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide. Clin. Pharmacol. Ther. 70, 58-65 (Pubitemid 32678803)
76. Bidstrup, T.B. et al. (2004) Rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide. Eur. J. Clin. Pharmacol. 60, 109-114 (Pubitemid 38626440)
77. Niemi, M. et al. (2000) Rifampin decreases the plasma concentrations and effects of repaglinide. Clin. Pharmacol. Ther. 68, 495-500
78. Hanefeld, M. (2001) Pharmacokinetics and clinical efficacy of pioglitazone. Int. J. Clin. Pract. Suppl. 121, 19-25
79. Jaakkola, T. et al. (2006) Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors. Basic Clin. Pharmacol. Toxicol. 99, 44-51 (Pubitemid 44034394)
80. Deng, L.J. et al. (2005) Effect of gemfibrozil on the pharmacokinetics of pioglitazone. Eur. J. Clin. Pharmacol. 61, 831-836
81. Jaakkola, T. et al. (2005) Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone. Clin. Pharmacol. Ther. 77, 404-414 (Pubitemid 40719268)
82. Tornio, A. et al. (2008) Trimethoprim and the CYP2C8*3 allele have opposite effects on the pharmacokinetics of pioglitazone. Drug Metab. Dispos. 36, 73-80
83. Kajosaari, L.I. et al. (2006) Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide. Eur. J. Clin. Pharmacol. 62, 217-223 (Pubitemid 43357580)
84. Scheen, A.J. (2007) Pharmacokinetic interactions with thiazolidinediones. Clin. Pharmacokinet. 46, 1-12
85. Cox, P.J. et al. (2000) Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans. Drug Metab. Dispos. 28, 772-780 (Pubitemid 30470827)
86. Baldwin, S.J. et al. (1999) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br. J. Clin. Pharmacol. 48, 424-432 (Pubitemid 29417728)
87. Niemi, M. et al. (2003) Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. Diabetologia 46, 1319-1323 (Pubitemid 37297200)
88. Niemi, M. et al. (2004) Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone. Clin. Pharmacol. Ther. 76, 239-249
89. Park, J.Y. et al. (2004) Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects. Br. J. Clin. Pharmacol. 58, 397-402
90. Kalliokoski, A. et al. (2008) No significant effect of SLCO1B1 polymorphism on the pharmacokinetics of rosiglitazone and pioglitazone. Br. J. Clin. Pharmacol. 65, 78-86 (Pubitemid 350265174)
91. Jaakkola, T. et al. (2006) Effect of rifampicin on the pharmacokinetics of pioglitazone. Br. J. Clin. Pharmacol. 61, 70-78 (Pubitemid 43381239)
92. Park, J.Y. et al. (2004) Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clin. Pharmacol. Ther. 75, 157-162
93. Scheen, A.J. (2010) Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes. Metab. 12, 648-658
94. Graefe-Mody, U. et al. (2010) Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin. Int. J. Clin. Pharmacol. Ther. 48, 367-374
95. Scheen, A.J. (2010) Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions. Clin. Pharmacokinet. 49, 573-588
96. Patel, C.G. et al. (2011) Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole. Clin. Pharmacol. 3, 13-25
97. Upreti, V.V. et al. (2011) Effect of rifampicin on the pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase-4 inhibitor, in healthy subjects. Br. J. Clin. Pharmacol. 72, 92-102
98. Vincent, S.H. et al. (2007) Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans. Drug Metab. Dispos. 35, 533-538 (Pubitemid 46513255)
99. Chu, X.Y. et al. (2007) Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J. Pharmacol. Exp. Ther. 321, 673-683
100. Krishna, R. et al. (2007) Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase- 4 inhibitor, in healthy male subjects. J. Clin. Pharmacol. 47, 165-174 (Pubitemid 46146482)
101. Miller, J.L. et al. (2006) The effect of MK-0431 on the pharmacokinetics of digoxin after concomitant administration for 10 days in healthy subjects. Clin. Pharmacol. Ther. 79, P24
102. He, H. et al. (2009) Absorption, metabolism, and excretion of [14C]vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans. Drug Metab. Dispos. 37, 536-544
103. Jayasagar, G. et al. (2002) Effect of cephalexin on the pharmacokinetics of metformin in healthy human volunteers. Drug Metab. Drug Interact. 19, 41-48
104. Pedersen, R.S. et al. (2006) The effects of human CYP2C8 genotype and fluvoxamine on the pharmacokinetics of rosiglitazone in healthy subjects. Br. J. Clin. Pharmacol. 62, 682-689 (Pubitemid 44749545)
105. Hruska, M.W. et al. (2005) The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects. Br. J. Clin. Pharmacol. 59, 70-79 (Pubitemid 40040098)