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Interactions Between Cyclosporin and Lipid-Lowering Drugs

Implications for Organ Transplant Recipients

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Abstract

Dyslipidaemia is more frequent in solid organ transplant recipients than in the general population, primarily as a result of immunosuppressive drug treatment. Both cyclosporin and corticosteroids are associated with dyslipidaemic adverse effects. In order to reduce the overall cardiovascular risk in these patients, lipid-lowering drugs have become widely used, especially HMG-CoA reductase inhibitors (statins). Cyclosporin, as well as most statins (lovastatin, simvastatin, atorvastatin and pravastatin) are metabolised by cytochrome P450 (CYP)3A4, so a bilateral pharmacokinetic interaction between these drugs is theoretically possible. However, results from several studies show that statins do not induce increased systemic exposure of cyclosporin. A small (but not clinically relevant) reduction in systemic exposure of cyclosporin has actually been shown in many studies. Cyclosporin-treated patients on the other hand show several-fold higher systemic exposure of all statins, both those that are metabolised by CYP3A4 and fluvastatin (metabolised by CYP2C9). Therefore, the mechanism for this interaction does not seem to be solely caused by inhibition of CYP3A4 metabolism, but it is probably also a result of inhibition of statin-transport in the liver, at least in part.

Other lipid-lowering drugs, such as fibric acid derivatives, bile acid sequestrants, probucol, fish oils and orlistat are also used in solid organ transplant recipients. Most of them do not interact with cyclosporin, but there are reports indicating that both probucol and orlistat may reduce cyclosporin bioavailablility to a clinically relevant degree. There is no information on possible interaction effects of cyclosporin on the pharmacokinetics of lipid-lowering drugs other than statins, but it is not likely that any clinical relevant interference exists with fish oil, orlistat, probucol or bile acid sequestrants.

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References

  1. Ojo AO, Hanson JA, Wolfe RA, et al. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000; 57(1): 307–13

    Article  PubMed  CAS  Google Scholar 

  2. Wierzbicki AS. The role of lipid lowering in transplantation. Int J Clin Pract 1999; 53(1): 54–9

    PubMed  CAS  Google Scholar 

  3. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 2001; 35(9): 1096–107

    Article  PubMed  CAS  Google Scholar 

  4. Omar MA, Wilson JP. FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother 2002; 36(2): 288–95

    Article  PubMed  CAS  Google Scholar 

  5. Jardine A. Assessing cardiovascular risk profile of immunosup-pressive agents. Transplantation 2001; 72 (12 Suppl.): S81–S8

    PubMed  CAS  Google Scholar 

  6. Christians U, Jacobsen W, Floren LC. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar? Pharmacol Ther 1998; 80(1): 1–34

    Article  PubMed  CAS  Google Scholar 

  7. Prueksaritanont T, Gorham LM, Ma B, et al. In vitro metabolism of simvastatin in humans [SBT] identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos 1997; 25(10): 1191–9

    PubMed  CAS  Google Scholar 

  8. Malinowski JM. Atorvastatin: a hydroxymethylglutaryl-coenzyme A reductase inhibitor. Am J Health Syst Pharm 1998; 55(21): 2253–67

    PubMed  CAS  Google Scholar 

  9. Mück W. Rational assessment of the interaction profile of cerivastatin supports its low propensity for drug interactions. Drugs 1998; 56 Suppl. 1: 15–23

    Article  PubMed  Google Scholar 

  10. Jacobsen W, Kirchner G, Hallensleben K, et al. Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver. Drug Metab Dispos 1999; 27(2): 173–9

    PubMed  CAS  Google Scholar 

  11. Jacobsen W, Kirchner G, Hallensleben K, et al. Small intestinal metabolism of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin and comparison with pravastatin. J Pharmacol Exp Ther 1999; 291(1): 131–9

    PubMed  CAS  Google Scholar 

  12. Singhvi SM, Pan HY, Morrison RA, et al. Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects. Br J Clin Pharmacol 1990; 29(2): 239–43

    Article  PubMed  CAS  Google Scholar 

  13. Fischer V, Johanson L, Heitz F, et al. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metab Dispos 1999; 27(3): 410–6

    PubMed  CAS  Google Scholar 

  14. Scripture CD, Pieper JA. Clinical pharmacokinetics of fluvastatin. Clin Pharmacokinet 2001; 40(4): 263–81

    Article  PubMed  CAS  Google Scholar 

  15. Zhang Y, Benet LZ. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet 2001; 40(3): 159–68

    Article  PubMed  CAS  Google Scholar 

  16. Bramow S, Ott P, Thomsen Nielsen F, et al. Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin). Pharmacol Toxicol 2001; 89(3): 133–9

    Article  PubMed  CAS  Google Scholar 

  17. Akhlaghi F, McLachlan AJ, Keogh AM, et al. Effect of simvastatin on cyclosporine unbound fraction and apparent blood clearance in heart transplant recipients. Br J Clin Pharmacol 1997; 44(6): 537–42

    Article  PubMed  CAS  Google Scholar 

  18. Garcia-Saiz M, Lopez-Gil A, Alfonso I, et al. Factors influencing cyclosporine blood concentration-dose ratio. Ann Pharmacother 2002; 36(2): 193–9

    Article  PubMed  CAS  Google Scholar 

  19. Olbricht C, Wanner C, Eisenhauer T, et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther 1997; 62(3): 311–21

    Article  PubMed  CAS  Google Scholar 

  20. Gullestad L, Nordal KP, Berg KJ, et al. Interaction between lovastatin and cyclosporine A after heart and kidney transplantation. Transplant Proc 1999; 31(5): 2163–5

    Article  PubMed  CAS  Google Scholar 

  21. Traindl O, Reading S, Franz M, et al. Low-dose lovastatin in hyperlipidemic kidney graft recipients with cyclosporine A. Transplant Proc 1992; 24(6): 2745–7

    PubMed  CAS  Google Scholar 

  22. Arnadottir M, Eriksson LO, Thysell H, et al. Plasma concentration profiles of simvastatin 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin. Nephron 1993; 65(3): 410–3

    Article  PubMed  CAS  Google Scholar 

  23. Arnadottir M, Eriksson LO, Germershausen JI, et al. Low-dose simvastatin is a well-tolerated and efficacious cholesterol-lowering agent in ciclosporin-treated kidney transplant recipients: double-blind, randomized, placebo-controlled study in 40 patients. Nephron 1994; 68(1): 57–62

    Article  PubMed  CAS  Google Scholar 

  24. Campana C, Iacona I, Regazzi MB, et al. Efficacy and pharmacokinetics of simvastatin in heart transplant recipients. Ann Pharmacother 1995; 29(3): 235–9

    PubMed  CAS  Google Scholar 

  25. Rehman MA, al-Sulaiman MH, Mousa DH, et al. Effects of simvastatin in hyperlipidemic renal transplant patients receiving cyclosporine. Transplantation 1995; 60(4): 397–9

    Article  PubMed  CAS  Google Scholar 

  26. Martinez Hernandez BE, Persaud JW, Varghese Z, et al. Low-dose simvastatin is safe in hyperlipidaemic renal transplant patients. Nephrol Dial Transplant 1993; 8(7): 637–41

    PubMed  CAS  Google Scholar 

  27. Capone D, Stanziale P, Gentile A, et al. Effects of simvastatin and pravastatin on hyperlipidemia and cyclosporin blood levels in renal transplant recipients. Am J Nephrol 1999; 19(3): 411–5

    Article  PubMed  CAS  Google Scholar 

  28. Pflugfelder PW, Huff M, Oskalns R, et al. Cholesterol-lowering therapy after heart transplantation: a 12-month randomized trial. J Heart Lung Transplant 1995; 14(4): 613–22

    PubMed  CAS  Google Scholar 

  29. Vanhaecke J, Van Cleemput J, Van Lierde J, et al. Safety and efficacy of low dose simvastatin in cardiac transplant recipients treated with cyclosporine. Transplantation 1994; 58(1): 42–5

    PubMed  CAS  Google Scholar 

  30. Lepre F, Rigby R, Hawley C, et al. A double-blind placebo controlled trial of simvastatin for the treatment of dyslipidaemia in renal allograft recipients. Clin Transplant 1999; 13(6): 520–5

    Article  PubMed  CAS  Google Scholar 

  31. Castelao AM, Grinyo JM, Castineiras MJ, et al. Effect of pravastatin in the treatment of hypercholesterolemia after renal transplantation under cyclosporine and prednisone. Transplant Proc 1995; 27(4): 2217–20

    PubMed  CAS  Google Scholar 

  32. Regazzi MB, Iacona I, Campana C, et al. Clinical efficacy and pharmacokinetics of HMG-CoA reductase inhibitors in heart transplant patients treated with cyclosporin A. Transplant Proc 1994; 26(5): 2644–5

    PubMed  CAS  Google Scholar 

  33. Park JW, Siekmeier R, Merz M, et al. Pharmacokinetics of pravastatin in heart-transplant patients taking cyclosporin A. Int J Clin Pharmacol Ther 2002; 10(10): 439–50

    Google Scholar 

  34. Schrama YC, Hene RJ, de Jonge N, et al. Efficacy and muscle safety of fluvastatin in cyclosporine-treated cardiac and renal transplant recipients: an exercise provocation test. Transplantation 1998; 66(9): 1175–81

    Article  PubMed  CAS  Google Scholar 

  35. Holdaas H, Hartmann A, Stenstrøm J, et al. Effect of fluvastatin for safely lowering atherogenic lipids in renal transplant patients receiving cyclosporine. Am J Cardiol 1995; 76(2): 102A-6A

    Article  Google Scholar 

  36. Martínez-Castelao A, Grinyo JM, Fiol C, et al. Fluvastatin and low-density lipoprotein oxidation in hypercholesterolemic renal transplant patients. Kidney Int Suppl 1999; 71: S231–4

    Article  PubMed  Google Scholar 

  37. Li PK, Mak TW, Wang AY, et al. The interaction of fluvastatin and cyclosporin A in renal transplant patients. Int J Clin Pharmacol Ther 1995; 33(4): 246–8

    PubMed  Google Scholar 

  38. Hadjigavriel M, Kyriakides G. Fluvastatin in renal transplantation. Transplant Proc 1997; 29(7): 3050

    Article  PubMed  CAS  Google Scholar 

  39. Goldberg R, Roth D. Evaluation of fluvastatin in the treatment of hypercholesterolemia in renal transplant recipients taking cyclosporine. Transplantation 1996; 62(11): 1559–64

    Article  PubMed  CAS  Google Scholar 

  40. Park JW, Siekmeier R, Lattke P, et al. Pharmacokinetics and pharmacodynamics of fluvastatin in heart transplant recipients taking cyclosporine A. J Cardiovasc Pharmacol Ther 2001; 6(4): 351–61

    Article  PubMed  CAS  Google Scholar 

  41. Demetriou D, Shabpar A, Bohmig G, et al. Beneficial effects of atorvastatin in the treatment of hyperlipidemia after renal transplantation. Wien Klin Wochenschr 2000; 112(8): 358–61

    PubMed  CAS  Google Scholar 

  42. Renders L, Mayer-Kadner I, Koch C, et al. Efficacy and drug interactions of the new HMG-CoA reductase inhibitors cerivastatin and atorvastatin in CsA-treated renal transplant recipients. Nephrol Dial Transplant 2001; 16: 141–6

    Article  PubMed  CAS  Google Scholar 

  43. Åsberg A, Hartmann A, Fjeldså E, et al. Bilateral pharmacokinetic interaction between cyclosporine A and atorvastatin in renal transplant recipients. Am J Transplant 2001; 1(4): 382–6

    Article  PubMed  Google Scholar 

  44. Miick W, Mai I, Fritsche L, et al. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther 1999; 65(3): 251–61

    Article  Google Scholar 

  45. Smith PF, Eydelloth RS, Grossman SJ, et al. HMG-CoA reductase inhibitor-induced myopathy in the rat: cyclosporine A interaction and mechanism studies. J Pharmacol Exp Ther 1991; 257(3): 1225–35

    PubMed  CAS  Google Scholar 

  46. Bogman K, Peyer AK, Torok M, et al. HMG-CoA reductase inhibitors and P-glycoprotein modulation. Br J Pharmacol 2001; 132(6): 1183–92

    Article  PubMed  CAS  Google Scholar 

  47. Boyd RA, Stern RH, Stewart BH, et al. Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol 2000; 40(1): 91–8

    Article  PubMed  CAS  Google Scholar 

  48. Hsiang B, Zhu Y, Wang Z, et al. A novel human hepatic organic anion transporting polypeptide (OATP2): identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem 1999; 274(52): 37161–8

    Article  PubMed  CAS  Google Scholar 

  49. Wu X, Whitfield LR, Stewart BH. Atorvastatin transport in the Caco-2 cell model: contributions of P-glycoprotein and the proton-monocarboxylic acid CO-transporter. Pharm Res 2000; 17(2): 209–15

    Article  PubMed  CAS  Google Scholar 

  50. Miller DB, Spence JD. Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet 1998; 34(2): 155–62

    Article  PubMed  CAS  Google Scholar 

  51. Pisanti N, Stanziale P, Imperatore P, et al. Lack of effect of gemfibrozil on cyclosporine blood concentrations in kidney-transplanted patients. Am J Nephrol 1998; 18(3): 199–203

    Article  PubMed  CAS  Google Scholar 

  52. Fehrman-Ekholm I, Jogestrand T, Angelin B. Decreased cyclosporine levels during gemfibrozil treatment of hyperlipidemia after kidney transplantation. Nephron 1996; 72(3): 483

    Article  PubMed  CAS  Google Scholar 

  53. Boissonnat P, Salen P, Guidollet J, et al. The long-term effects of the lipid-lowering agent fenofibrate in hyperlipidemic heart transplant recipients. Transplantation 1994; 58(2): 245–7

    PubMed  CAS  Google Scholar 

  54. deLorgeril M, Boissonnat P, Bizollon CA, et al. Pharmacokinetics of cyclosporine in hyperlipidaemic long-term survivors of heart transplantation: lack of interaction with the lipid-lowering agent, fenofibrate. Eur J Clin Pharmacol 1992; 43(2): 161–5

    Article  PubMed  CAS  Google Scholar 

  55. Jensen RA, Lal SM, Diaz-Arias A, et al. Does cholestyramine interfere with cyclosporine absorption? A prospective study in renal transplant patients. ASAIO J 1995; 41(3): M704–6

    Article  PubMed  CAS  Google Scholar 

  56. Keogh A, Day R, Critchley L, et al. The effect of food and cholestyramine on the absorption of cyclosporine in cardiac transplant recipients. Transplant Proc 1988; 20(1): 27–30

    PubMed  CAS  Google Scholar 

  57. Gallego C, Sanchez P, Planells C, et al. Interaction between probucol and cyclosporine in renal transplant patients. Ann Pharmacother 1994; 28(7–8): 940–3

    PubMed  CAS  Google Scholar 

  58. Wakasugi H, Yoshimoto M, Aoki M, et al. Effect of probucol on the concentration of cyclosporin A in patients with nephrotic syndrome. Nippon Jinzo Gakkai Shi 2001; 43(7): 595–9

    PubMed  CAS  Google Scholar 

  59. Sugimoto K, Sakamoto K, Fujimura A. Decrease in oral bioavailability of cyclosporin A by coadministration of probucol in rats. Life Sci 1997; 60(3): 173–9

    Article  PubMed  CAS  Google Scholar 

  60. Bays HE, Dujovne CA. Drugs for treatment of patients with high cholesterol blood levels and other dyslipidemias. Prog Drug Res 1994; 43: 9–41

    PubMed  CAS  Google Scholar 

  61. Homan van der Heide JJ, Bilo HJ, Donker JM, et al. Effect of dietary fish oil on renal function and rejection in cyclosporine-treated recipients of renal transplants. N Engl J Med 1993; 329(11): 769–73

    Article  Google Scholar 

  62. Homan van der Heide JJ, Bilo HJ, Donker AJ, et al. Dietary supplementation with fish oil modifies renal reserve filtration capacity in postoperative, cyclosporin A-treated renal transplant recipients. Transpl Int 1990; 3(3): 171–5

    Article  PubMed  CAS  Google Scholar 

  63. Homan van der Heide JJ, Bilo HJ, Donker AJ, et al. The effects of dietary supplementation with fish oil on renal function and the course of early postoperative rejection episodes in cyclosporine-treated renal transplant recipients. Transplantation 1992; 54(2): 257–63

    PubMed  CAS  Google Scholar 

  64. Kovarik JM, Mueller EA, vanBree JB, et al. Cyclosporine pharmacokinetics and variability from a microemulsion formulation: a multicenter investigation in kidney transplant patients. Transplantation 1994; 58(6): 658–63

    PubMed  CAS  Google Scholar 

  65. Muls E, Kolanowski J, Scheen A, et al. The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled, multicentre study. Int J Obes Relat Metab Disord 2001; 25(11): 1713–21

    Article  PubMed  CAS  Google Scholar 

  66. Nägele H, Petersen B, Bonacker U, et al. Effect of orlistat on blood cyclosporin concentration in an obese heart transplant patient. Eur J Clin Pharmacol 1999; 55(9): 667–9

    Article  PubMed  Google Scholar 

  67. le Beller C, Bezie Y, Chabatte C, et al. Co-administration of orlistat and cyclosporine in a heart transplant recipient. Transplantation 2000; 70(10): 1541–2

    Article  PubMed  Google Scholar 

  68. Schnetzler B, Kondo-Oestreicher M, Vala D, et al. Orlistat decreases the plasma level of cyclosporine and may be responsible for the development of acute rejection episodes. Transplantation 2000; 70(10): 1540–1

    Article  PubMed  CAS  Google Scholar 

  69. Errasti P, Garcia I, Lavilla J, et al. Reduction in blood cyclosporine concentration by orlistat in two renal transplant patients. Transplant Proc 2002; 34(1): 137

    Article  PubMed  CAS  Google Scholar 

  70. Barbara D, Orsini P, Pallini S, et al. Obesity in transplant patients: case report showing interference of orlistat with absorption of cyclosporine and review of literature. Endocr Pract 2002; 8(2): 124

    Google Scholar 

  71. Zhi J, Moore R, Kanitra L, et al. Pharmacokinetic evaluation of the possible interaction between selected concomitant medications and orlistat at steady state in healthy subjects. J Clin Pharmacol 2002; 42(9): 1011

    PubMed  CAS  Google Scholar 

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Acknowledgements

Dr Åsberg holds a part-time post-doctorate position at the Laboratory for Renal Physiology, Rikshospitalet, Norway, which is founded by a grant from Medinnova SF. Dr Åsberg also works as Medical Advisor for Roche Norway AS. He would also like to acknowledge Professor Anders Hartmann for critically reviewing the paper.

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  1. Laboratory for Renal Physiology, Section of Nephrology, C1 1027, Medical Department, The National Hospital, N-0027, Oslo, Norway

    Anders Åsberg

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Åsberg, A. Interactions Between Cyclosporin and Lipid-Lowering Drugs. Drugs 63, 367–378 (2003). https://doi.org/10.2165/00003495-200363040-00003

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