Clinical Pharmacokinetics

, Volume 41, Issue 14, pp 1195–1211

Interactions Between Antiretroviral Drugs and Drugs Used for the Therapy of the Metabolic Complications Encountered During HIV Infection

Review Articles Drug Interactions

Abstract

Treatment of HIV infection with potent combination antiretroviral therapy has resulted in major improvement in overall survival, immune function and the incidence of opportunistic infections. However, HIV infection and treatment has been associated with the development of metabolic complications, including hyperlipidaemia, diabetes mellitus, hypertension, lipodystrophy and osteopenia. Safe pharmacological treatment of these complications requires an understanding of the drug-drug interactions between antiretroviral drugs and the drugs used in the treatment of metabolic complications. Since formal studies of most of these interactions have not been performed, predictions must be based on our understanding of the metabolism of these agents.

All HIV protease inhibitors are metabolised by and inhibit cytochrome P450 (CYP) 3A4. Ritonavir is the most potent inhibitor of CYP3A4. Ritonavir and nelfinavir also induce a host of CYP isoforms as well as some conjugating enzymes. The non-nucleoside reverse transcriptase inhibitor delavirdine potently inhibits CYP3A4, whereas nevirapine and efavirenz are inducers of CYP3A4.

Drug interaction studies have been performed with HIV protease inhibitors and HMG-CoA reductase inhibitors. Coadministration of ritonavir plus saquinavir to HIV-seronegative volunteers resulted in increased exposure to simvastatin acid by 3059%. Atorvastatin exposure increased by 347%, but exposure to active atorvastatin increased by only 79%. Conversely, pravastatin exposure decreased by 50%. Similar results have been obtained with combinations of simvastatin and atorvastatin with other HIV protease inhibitors. Thus, the lactone prodrugs simvastatin and lovastatin should not be used with HIV protease inhibitors. Atorvastatin may be used with caution.

Although there are no formal studies available, calcium channel antagonists and repaglinide may have significant interactions and toxicity when used with HIV protease inhibitors because of their metabolism by CYP3A4. Sulfonylurea drugs utilise mainly CYP2C9 for metabolism, and this isoenzyme may be induced by ritonavir and nelfinavir with a resulting decrease in efficacy of the sulfonyl-urea. Losartan may have increased effect when coadministered with ritonavir and nelfinavir because of the induction of CYP2C9 and the expected increase in formation of the active metabolite, E-3174.

Overall, well-designed drug-drug interaction studies at steady state are needed to determine whether antiretroviral drugs may be safely coadministered with many of the drugs used in the treatment of the metabolic complications of HIV infection.

References

  1. 1.
    Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853–60PubMedGoogle Scholar
  2. 2.
    Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998; 12: F51–8PubMedGoogle Scholar
  3. 3.
    Carr A, Samaras K, Chisholm DJ, et al. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998; 352: 1881–3Google Scholar
  4. 4.
    Viraben R, Aquilina C. Indinavir-associated lipodystrophy. AIDS 1998; 12: F37–9PubMedGoogle Scholar
  5. 5.
    Miller KD, Jones E, Yanovski JA, et al. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 1998; 351: 871–5PubMedGoogle Scholar
  6. 6.
    Lo JC, Mulligan K, Tai VW, et al. Buffalo hump in men with HIV-1 infection. Lancet 1998; 351: 867–70PubMedGoogle Scholar
  7. 7.
    Walli R, Herfort O, Michl GM, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1 infected patients. AIDS 1998; 12: F167–73PubMedGoogle Scholar
  8. 8.
    Yarasheski KE, Tebas P, Sigmund C, et al. Insulin resistance in HIV protease inhibitor-associated diabetes. J Acquir Immune Defic Syndr 1999; 21: 209–16PubMedGoogle Scholar
  9. 9.
    Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999; 353: 2093–9PubMedGoogle Scholar
  10. 10.
    Segerer S, Bogner JR, Walli R, et al. Hyperlipidemia under treatment with proteinase inhibitors. Infection 1999; 2: 77–81Google Scholar
  11. 11.
    Danner SA, Carr A, Leonard JM, et al. A short-term study of the safety, pharmacokinetics and efficacy of ritonavir, an inhibitor of HIV-1 protease. N Engl J Med 1995; 333: 1528–33PubMedGoogle Scholar
  12. 12.
    Behrens G, Dejam A, Schmidt H, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS 1999; 13: F63–70PubMedGoogle Scholar
  13. 13.
    Periard D, Telenti A, Sudre P, et al. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. Circulation 1999; 100: 700–5PubMedGoogle Scholar
  14. 14.
    Hewitt RG, Thompson IV WM, Chu A, et al. Indinavir, not nelfinavir, is associated with systemic hypertension when compared to no protease inhibitor therapy [abstract 658]. In: Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; 2001 Feb 4–8; Chicago (IL)Google Scholar
  15. 15.
    Cattelan AM, Trevenzoli M, Sasset L, et al. Indinavir and systemic hypertension. AIDS 2001; 15: 805–7PubMedGoogle Scholar
  16. 16.
    Tebas P, Powderly WG, Claxton S, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000; 14: F63–7PubMedGoogle Scholar
  17. 17.
    Scribner AN, Troia-Cancio PV, Cox BA, et al. Osteonecrosis in HIV: a case-control study. J Acquir Immune Defic Syndr 2000; 25: 19–25PubMedGoogle Scholar
  18. 18.
    Panel on Clinical Practices for Treatment of HIV Infection, Department of Health and Human Services and the Henry J Kaiser Family Foundation. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents; 2002 Feb 4 [online]. Available from URL: http://www.hivatis.org. [Accessed 2002 Sep 16]
  19. 19.
    Henry K, Melroe H, Huebusch J, et al. Severe premature coronary artery disease with protease inhibitors [abstract]. Lancet 1998; 351: 1328PubMedGoogle Scholar
  20. 20.
    Flynn TE, Bricker LA. Myocardial infarction in HIV-1 infected men receiving protease inhibitors [letter]. Ann Intern Med 1999; 131: 548PubMedGoogle Scholar
  21. 21.
    Sullivan AK, Nelson MR, Moyle GJ, et al. Coronary artery disease occurring with protease inhibitor therapy. Int J STD AIDS 1998; 11: 711–2Google Scholar
  22. 22.
    David MH, Hornung R, Fichtenbaum CJ. A case-control study of ischemic cardiovascular disease risk factors in persons with HIV infection and proven coronary artery disease. Clin Infect Dis 2002; 34: 98–102PubMedGoogle Scholar
  23. 23.
    Flexner C. HIV protease inhibitors. N Engl J Med 1998; 338: 1281–92PubMedGoogle Scholar
  24. 24.
    Erickson DA, Mather G, Trager WF, et al. Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos 1999; 27: 1488–95PubMedGoogle Scholar
  25. 25.
    Smith PF, DiCenzo R, Morse GD. Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors. Clin Pharmacokinet 2001; 40: 893–905PubMedGoogle Scholar
  26. 26.
    Guengerich FP, Gillam EMJ, Martin MV, et al. The importance of cytochrome P450 3A enzymes in drug metabolism. In: Schering Foundation Workshop. Assessment of the use of single cytochrome P450 enzymes in drug research. Berlin: Springer-Verlag, 1994: 161–86Google Scholar
  27. 27.
    Wolf CR, Smith G. Pharmacogenetics. Br Med Bull 1999; 55: 366–86PubMedGoogle Scholar
  28. 28.
    Decker CJ, Laitinen LM, Bridson GW, et al. Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions. J Pharm Sci 1998; 87: 803–7PubMedGoogle Scholar
  29. 29.
    Palkama VJ, Ahonen J, Neuvonen PJ, et al. Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. Clin Pharmacol Ther 1999; 66: 33–9PubMedGoogle Scholar
  30. 30.
    Hsu A, Granneman GR, Bertz RJ. Ritonavir: clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet 1998; 35: 275–91PubMedGoogle Scholar
  31. 31.
    Frye RF, Bertz RJ, Granneman GR, et al. Effect of ritonavir on CYP1A2, 2C19, and 2E1 activities in vivo [abstract]. Clin Pharmacol Ther 1998; 63: 148Google Scholar
  32. 32.
    Bertz RJ, Cao G, Cavanaugh JH, et al. Effect of ritonavir on the pharmacokinetics of desipramine [abstract Mo.B.1201]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver (BC).Google Scholar
  33. 33.
    von Moltke LL, Greenblatt DJ, Granda BW, et al. Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol 2001; 41: 85–91Google Scholar
  34. 34.
    Fiske WD, Benedek IH, White SJ, et al. Pharmacokinetic interaction between efavirenz and nelfinavir mesylate in healthy volunteers [abstract 349]. Program and Abstracts of the 5th Conference on Retroviruses and Opportunistic Infections; 1998 February 1–5; Chicago (IL)Google Scholar
  35. 35.
    Voorman RL, Payne NA, Wienkers LC, et al. Interaction of delavirdine with human liver microsomal cytochrome P450: inhibition of CYP2C9, CYP2C19, and CYP2D6. Drug Metab Dispos 2001; 29: 41–7PubMedGoogle Scholar
  36. 36.
    Voorman RL, Maio SM, Payne NA, et al. Microsomal metabolism of delavirdine: evidence for mechanism-based inactivation of human cytochrome P450 3A. J Pharmacol Exp Ther 1998; 287: 381–8PubMedGoogle Scholar
  37. 37.
    Lehmann JM, McKee DD, Watson MA, et al. The human orphan nuclear receptor PXR is activated by compound that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 1998; 102: 1016–23PubMedGoogle Scholar
  38. 38.
    Dussault I, Lin M, Hollister K, et al. Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR. J Biol Chem 2001; 36: 33309–12Google Scholar
  39. 39.
    Drocourt L, Pascussi JM, Assenat E, et al. Calcium channel modulators of the dihydropyridine family are human pregnane X receptor activators and inducers of CYP3A, CYP2B, and CYP2C in human hepatocytes. Drug Metab Dispos 2001; 29: 1325–31PubMedGoogle Scholar
  40. 40.
    Shibata N, Gao W, Okamoto H, et al. In-vitro and in-vivo pharmacokinetic interactions of amprenavir, an HIV protease inhibitor, with other current HIV protease inhibitors in rats. J Pharm Pharmacol 2002; 54: 221–9PubMedGoogle Scholar
  41. 41.
    Weaver RJ. Assessment of drug-drug interactions: concepts and approaches. Xenobiotica 2001; 31: 499–538PubMedGoogle Scholar
  42. 42.
    von Moltke LL, Greenblatt DJ, Schmider J, et al. In vitro approaches to predicting drug interactions in vivo. Biochem Pharmacol 1998; 55: 113–22Google Scholar
  43. 43.
    Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999; 341: 498–511PubMedGoogle Scholar
  44. 44.
    Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Clin Pharmacokinet 1997; 32: 403–25PubMedGoogle Scholar
  45. 45.
    Everett DW, Chando TJ, Didonato GC, et al. Biotransformation of pravastatin sodium in humans. Drug Metab Dispos 1991; 19: 740–8PubMedGoogle Scholar
  46. 46.
    Transon C, Leemann T, Vogt N, et al. In vivo inhibition profile of cytochrome p450tb (CYP2C9) by (±)-fluvastatin. Clin Pharmacol Ther 1995; 58: 412–7PubMedGoogle Scholar
  47. 47.
    Jacobsen W, Kuhn B, Solder A, et al. Factorization is the critical first step in the disposition of the 3-hydroxy-3methylglutaryl-CoA reductase inhibitor atorvastatin. Drug Metab Dispos 2000; 28: 1369–78PubMedGoogle Scholar
  48. 48.
    Vyas KP, Kari PH, Pitzenberger SM, et al. Biotransformation of lovastatin I: structure elucidation of in vitro and in vivo metabolites in the rat and mouse. Drug Metab Dispos 1990; 18: 203–11PubMedGoogle Scholar
  49. 49.
    Jacobsen W, Kirchner G, Hallensleben K, et al. Small intestinal metabolism of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin in comparison with pravastatin. J Pharmacol Exp Ther 1999; 291: 131–9PubMedGoogle Scholar
  50. 50.
    Trenton C, Lee Mann T, Dater P. In vitro comparative inhibition profiles of major human drug metabolizing cytochrome P450 isozymes (CYP2C9, CYP2D6, and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharm 1996; 50: 209–15Google Scholar
  51. 51.
    Neuvonen PJ, Saliva KM. Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996; 60: 54–61PubMedGoogle Scholar
  52. 52.
    Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63: 332–41PubMedGoogle Scholar
  53. 53.
    Prueksaritanon T, Gorham LM, Ma B, et al. In vitro metabolism of simvastatin in humans: identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos 1997; 25: 1191–9Google Scholar
  54. 54.
    Arnadottir M, Eriksson LO, Thysell H, et al. Plasma concentration profiles of simvastatin 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor activity in kidney transplant recipients with and without ciclosporin. Nephron 1993; 65: 410–3PubMedGoogle Scholar
  55. 55.
    Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64: 58–65PubMedGoogle Scholar
  56. 56.
    Fichtenbaum CJ, Gerber JG, Rosenkranz S, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG study A5047. AIDS 2002; 16: 569–77PubMedGoogle Scholar
  57. 57.
    Hsyu PH, Schultz-Smith MD, Lillibridge JH, et al. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001; 45: 3445–50PubMedGoogle Scholar
  58. 58.
    Carr RA, Andre AK, Bertz RJ, et al. Concomitant administration of ABT-378/ritonavir (ABT-378/r) results in a clinically important pharmacokinetics (PK) interaction with atorvastatin (ATO) but not pravastatin (PRA) [abstract 1644]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto, CanadaGoogle Scholar
  59. 59.
    Martin CM, Hoffman V, Berggren RE. Rhabdomyolysis in a patient receiving simvastatin concurrently with highly active antiretroviral therapy [abstract 1297]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto, CanadaGoogle Scholar
  60. 60.
    Wong PW, Dillard TA, Kroenke K. Multiple organ toxicity from addition of erythromycin to long-term lovastatin therapy. South Med J 1998; 91: 202–5PubMedGoogle Scholar
  61. 61.
    Schmassmann-Suhijar D, Bullingham R, Gasser R, et al. Rhabdomyolysis due to interaction of simvastatin with mibefradil. Lancet 1998; 351: 1929–30PubMedGoogle Scholar
  62. 62.
    Jacobson RH, Wang P, Glueck CJ. Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone [letter]. JAMA 1997; 277: 296PubMedGoogle Scholar
  63. 63.
    Horn M. Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals [letter]. Arch Dermatol 1996; 132: 1254PubMedGoogle Scholar
  64. 64.
    Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med 1995; 333: 664–5PubMedGoogle Scholar
  65. 65.
    Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998; 46: 49–53PubMedGoogle Scholar
  66. 66.
    Kantola T, Backman JT, Niemi M, et al. Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol 2000; 56: 225–9PubMedGoogle Scholar
  67. 67.
    Fruchart JC, Brewer HB, Leitersdorf E. Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Fibrate Consensus Group. Am J Cardiol 1998; 81: 912–7PubMedGoogle Scholar
  68. 68.
    Minnich A, Tian N, Byan L, et al. A potent PPARα agonist stimulates mitochondrial fatty acid β-oxidation in liver and skeletal muscle. Am J Physiol Endocrinol Metab 2001; 280: E270–9PubMedGoogle Scholar
  69. 69.
    Guay DRP. Micronized fenofibrate: a new fibric acid hypolipidemic agent. Ann Pharmacother 1999; 33: 1083–103PubMedGoogle Scholar
  70. 70.
    Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45: 525–38PubMedGoogle Scholar
  71. 71.
    Relling MV, Aoyama T, Gonzales FJ, et al. Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily. J Pharmacol Exp Ther 1990; 252: 442–7PubMedGoogle Scholar
  72. 72.
    Niemi M, Backman JT, Neuvonen M, et al. Effect of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Clin Pharmacol Ther 2001; 69: 194–200PubMedGoogle Scholar
  73. 73.
    Stockley IH. Drug interactions. 5th ed. London: Pharmaceutical Press, 1999: 519Google Scholar
  74. 74.
    Johnson JF, Dobmeier ME. Symptomatic hypoglycemia secondary to a glipizide-trimethoprim/sulfamethoxazole drug interaction. DCIP 1990; 24: 250–1Google Scholar
  75. 75.
    Wing LM, Miners JO. Clotrimoxazole as an inhibitor of oxidative drug metabolism: effect of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition. Br J Clin Pharmacol 1985; 20: 482–5PubMedGoogle Scholar
  76. 76.
    Knoell KR, Young TM, Cousins ES. Potential interaction involving warfarin and ritonavir. Ann Pharmacother 1998; 32: 1299–302PubMedGoogle Scholar
  77. 77.
    Kunze KL, Wienkers LC, Thummel KE, et al. Warfarinfluconazole: I. inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies. Drug Metab Dispos 1996; 24: 414–21PubMedGoogle Scholar
  78. 78.
    Guay DRP. Repaglinide, a novel, short-acting hypoglycemic agent for type 2 diabetes mellitus. Pharmacotherapy 1998; 18: 1195–204PubMedGoogle Scholar
  79. 79.
    Cully CR, Jarvis B. Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus. Drugs 2001; 61: 1625–60Google Scholar
  80. 80.
    Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996; 30: 359–71PubMedGoogle Scholar
  81. 81.
    Olefsky JM, Saltiel AR. PPAR gamma and the treatment of insulin resistance. Trends Endocrine Metab 2000; 11: 362–8Google Scholar
  82. 82.
    Watkins PB, Whitcomb RW. Hepatic dysfunction associated with troglitazone. N Engl J Med 1998; 338: 916–7PubMedGoogle Scholar
  83. 83.
    Loi CM, Young M, Randinitis E, et al. Clinical pharmacokinetics of troglitazone. Clin Pharmacokinet 1999; 37: 91–104PubMedGoogle Scholar
  84. 84.
    Sahi J, Hamilton G, Sinz M, et al. Effect of troglitazone on cytochrome P450 enzymes in primary cultures of human and rat hepatocytes. Xenobiotica 2000; 30: 273–84PubMedGoogle Scholar
  85. 85.
    Ramachandran V, Kostrubsky VE, Komoroski BJ, et al. Troglitazone increases cytochrome P-450 3A protein and activity in primary cultures of human hepatocytes. Drug Metab Dispos 1999; 27: 1194–9PubMedGoogle Scholar
  86. 86.
    Balfour JA, Plosker GL. Rosiglitazone. Drugs 1999; 57: 921–30PubMedGoogle Scholar
  87. 87.
    Baldwin SJ, Clarke SE, Chenery RJ. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol 1999; 48: 424–32PubMedGoogle Scholar
  88. 88.
    Pioglitazone product information. Physicians Desk Reference 55th Edition. Lincolnshire (IL): Takeda Pharmaceuticals, 2001: 3171–5Google Scholar
  89. 89.
    Johnson DL, Qian D, Briggs W, et al. Hypertension (HTN) in HIV patients with metabolic dysregulation [abstract 35]. 7th Conference on Retroviruses and Opportunistic Infections; 2000, San Francisco (CA).Google Scholar
  90. 90.
    Prichard BN, Graham BR, Cruickshank JM. New approaches to the uses of beta blocking drugs in hypertension. J Hum Hypertens 2000; 14 Suppl. 1: S63–8PubMedGoogle Scholar
  91. 91.
    McDevitt DG. Comparison of pharmacokinetic properties of beta-adrenoceptor blocking drugs. Eur Heart J 1987; 8 Suppl. M: 9–14PubMedGoogle Scholar
  92. 92.
    Sklar J, Johnston GD, Overlie P, et al. The effects of a cardioselective (metoprolol) and a nonselective (propranolol) beta-adrenergic blocker on the response to dynamic exercise in normal men. Circulation 1982; 65: 894–9PubMedGoogle Scholar
  93. 93.
    Otton SV, Crewe HK, Lennard MS, et al. Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes. J Pharmacol Exp Ther 1988; 247: 242–7PubMedGoogle Scholar
  94. 94.
    Edeki TI, He H, Wood AJ. Pharmacogenetic explanation for excessive beta-blockade following timolol eye drops: potential for oral-ophthalmic drug interaction. JAMA 1995; 274: 1611–3PubMedGoogle Scholar
  95. 95.
    Ward SA, Walle T, Walle UK, et al. Propranolol’s metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities. Clin Pharmacol Ther 1989; 45: 72–9PubMedGoogle Scholar
  96. 96.
    Masubuchi Y, Hosokawa S, Horie T, et al. Cytochrome P450 isozymes involved in propranolol metabolism in human liver microsomes: the role of CYP2D6 as ring-hydroxylase and CYP1A2 as N-desisopropylase. Drug Metab Dispos 1994; 22: 909–15PubMedGoogle Scholar
  97. 97.
    Song JC, White CM. Pharmacologic, pharmacokinetic, and therapeutic differences among angiotensin II receptor antagonists. Pharmacother 2000; 20: 130–9Google Scholar
  98. 98.
    Timmermans PB. Angiotensin II receptor antagonists: an emerging new class of cardiovascular therapeutics. Hypertens Res 1999; 22: 147–53PubMedGoogle Scholar
  99. 99.
    Shusterman NH. Safety and efficacy of eprosartan, a new angiotensin II receptor blocker. Am Heart J 1999; 138: 238–45PubMedGoogle Scholar
  100. 100.
    Israili ZH. Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. J Hum Hypertens 2000; 14 Suppl. 1: S73–86PubMedGoogle Scholar
  101. 101.
    Yasar U, Tybring G, Hidestrand M, et al. Role of CYP2C9 polymorphism in losartan oxidation. Drug Metab Dispos 2001; 29: 1051–6PubMedGoogle Scholar
  102. 102.
    Goa KL, Wagstaff AJ. Losartan potassium: a review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 1996; 51: 820–45PubMedGoogle Scholar
  103. 103.
    Kazierad DJ, Martin DE, Blum RA, et al. Effect of fluconazole on the pharmacokinetics of eprosartan and losartan in healthy male volunteers. Clin Pharmacol Ther 1997; 62: 417–25PubMedGoogle Scholar
  104. 104.
    Kaukonen KM, Olkkola KT, Neuvonen PJ. Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. Eur J Clin Pharmacol 1998; 53: 445–9PubMedGoogle Scholar
  105. 105.
    McCrea JB, Cribb A, Rushmore T, et al. Phenotypic and genotypic investigations of a healthy volunteer deficient in the conversion of losartan to its active metabolite E-3174. Clin Pharmacol Ther 1999; 65: 348–52PubMedGoogle Scholar
  106. 106.
    Spielberg S, McCrea J, Cribb A, et al. A mutation in CYP2C9 is responsible for decreased metabolism of losartan [abstract]. Clin Pharmacol Ther 1996; 59: 215Google Scholar
  107. 107.
    Abernathy DR, Schwartz JB. Calcium-antagonist drugs. N Engl J Med 1999; 341: 1447–57Google Scholar
  108. 108.
    Guengerich FP, Bnan WR, Iwasaki M, et al. Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 IIIA4. J Med Chem 1991; 34: 1838–44PubMedGoogle Scholar
  109. 109.
    Pichard L, Gillett G, Fabre I, et al. Identification of the rabbit and human cytochrome P-450IIIA as the major enzymes involved in the N-demethylation of diltiazem. Drug Metab Dispos 1990; 18: 711–9PubMedGoogle Scholar
  110. 110.
    Kroemer HK, Gautier J-C, Beaune P, et al. Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol 1993; 348: 332–7PubMedGoogle Scholar
  111. 111.
    Klein HO, Lang R, Weiss E, et al. The influence of verapamil on serum digoxin concentration. Circulation 1982; 65: 998–1003PubMedGoogle Scholar
  112. 112.
    Jones DR, Gorski JC, Hamman MA, et al. Diltiazem inhibition of cytochrome P-450 3A activity is due to metabolite intermediate complex formation. J Pharmacol Exp Ther 1999; 290: 1116–25PubMedGoogle Scholar
  113. 113.
    Lundahl J, Regardh CG, Edgar B, et al. Effects of grapefruit juice ingestion: pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol 1997; 52: 139–45PubMedGoogle Scholar
  114. 114.
    Takanaga H, Ohnishi A, Murakami H, et al. Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects. Clin Pharmacol Ther 2000; 67: 201–14PubMedGoogle Scholar
  115. 115.
    Uno T, Ohkubo T, Sugawara K, et al. Effects of grapefruit juice on the stereoselective disposition of nicardipine in humans: evidence for dominant presystemic elimination at the gut site. Eur J Clin Pharmacol 2000; 56: 643–9PubMedGoogle Scholar
  116. 116.
    Vincent J, Harris SI, Foulds G, et al. Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine. Br J Clin Pharmacol 2000; 50: 455–63PubMedGoogle Scholar
  117. 117.
    Heinig R, Adelmann HG, Ahr G. The effect of ketoconazole on the pharmacokinetics, pharmacodynamics and safety of nisoldipine. Eur J Clin Pharmacol 1999; 55: 57–60PubMedGoogle Scholar
  118. 118.
    Jalava K-M, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma concentrations and effects of felodipine. Clin Pharmacol Ther 1997; 61: 410–5PubMedGoogle Scholar
  119. 119.
    Carr A, Miller J, Eisman JA, et al. Osteopenia in HIV-infected men: association with asymptomatic lactic academia and lower weight pre-antiretroviral therapy. AIDS 2001; 15: 703–9PubMedGoogle Scholar
  120. 120.
    Watts NB. Treatment of osteoporosis with bisphosphonates. Rheum Dis Clin North Am 2001; 27: 197–214PubMedGoogle Scholar
  121. 121.
    Porras AG, Holland SD, Gertz BJ. Pharmacokinetics of alendronate. Clin Pharmacokinet 1999; 36: 315–28PubMedGoogle Scholar
  122. 122.
    Dunn CJ, Goa KL. Risedronate: a review of its pharmacological properties and clinical use in resorptive bone disease. Drugs 2001; 61: 685–712PubMedGoogle Scholar
  123. 123.
    Snyder KR, Sparano N, Malinowksi JM. Raloxifene hydrochloride. Am J Health Syst Pharm 2000; 57: 1669–75PubMedGoogle Scholar
  124. 124.
    Ouellet D, Hsu A, Qian J, et al. Effect of ritonavir on the pharmacokinetics of ethinyl estradiol in healthy female volunteers. Br J Clin Pharmacol 1998; 46: 111–6PubMedGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Division of Infectious DiseasesUniversity of Cincinnati College of MedicineCincinnatiUSA
  2. 2.Divisions of Clinical Pharmacology and Infectious DiseasesUniversity of Colorado Health Sciences CenterDenverUSA
  3. 3.University of Colorado Health Sciences CenterDenverUSA

Personalised recommendations