Cyclosporine (CyA) is a well-known immunosuppressant with a narrow therapeutic window. Its bioavailability is affected by many other traditional drugs and herbal extracts. Cytochrome P-450 isoenzymes CYP3A4 and CYP3A5 and protein P-glycoprotein (P-gp) are involved in CyA bioavailability. Interactions of CyA with herbal extracts are not well known, but, given their increased concomitant use, it is important to know which extracts, many of which are commonly self-prescribed, can affect CyA blood concentrations. Decreased CyA blood concentration has been shown with St John’s wort in case reports and, in vivo animal studies, with ginger, liquorice, scutellariae radix, and quercetin. Increased CyA concentration has been reported in patients with grapefruit juice, chamomile, or berberine, and with cannabidiol or resveratrol in animal studies. Effects of Echinacea and Serenoa repens on CyA levels have not been shown consistently, but concomitant use should be avoided. Although findings from animal studies cannot be directly translated into humans, avoiding concomitant use of herbal extracts is prudent until human clinical studies have ruled out any possible interaction. Clinicians should interview their patients carefully about their use of herbal supplements before CyA administration, and those receiving CyA should be warned about possible interactions between herbal preparations and CyA. 1. Introduction In 1972, cyclosporine (CyA) was discovered and identified as a new antifungal drug with unexpected immunologic characteristics. Subsequently, the effect of CyA on lymphocyte activation was demonstrated [1]. Since this discovery, CyA was introduced as a new immunosuppressant therapy and, in the last three decades, has been widely used in transplant recipients to prevent rejection and in the treatment of autoimmune diseases, with successful results. CyA is also widely used in the treatment of psoriasis, atopic dermatitis, and other dermatological disorders. CyA is a lipophilic cyclic polypeptide that selectively inhibits the adaptive immune response. This activity is exerted through CyA binding to cyclophilin, inhibition of calcineurin, and nuclear factor transcription, with a subsequent alteration in T-cell activation. The lipophilic nature of CyA required the development of a triphasic microemulsion preparation with higher hydrophilicity to reduce the interindividual variability in intestinal absorption. CyA is metabolized in the liver and small intestine by isoenzymes CYP3A4 and CYP3A5 of the cytochrome P-450 family [2]. Protein P-glycoprotein (P-gp), an
References
[1]
J. F. Borel, “Comparative study of in vitro and in vivo drug effects on cell mediated cytotoxicity,” Immunological Communications, vol. 31, no. 4, pp. 631–641, 1976.
[2]
T. Kronbach, V. Fischer, and U. A. Meyer, “Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs,” Clinical Pharmacology and Therapeutics, vol. 43, no. 6, pp. 630–635, 1988.
[3]
D. Leveque and F. Jehl, “P-glycoprotein and pharmacokinetics,” Anticancer Research, vol. 15, no. 2, pp. 331–336, 1995.
[4]
V. J. Wacher, C.-Y. Wu, and L. Z. Benet, “Overlapping substrate specificities and tissue distribution of cytochrome p450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy,” Molecular Carcinogenesis, vol. 13, no. 3, pp. 129–134, 1995.
[5]
R. S. Gaston, “Maintenance immunosuppression in the renal transplant recipient: an overview,” American Journal of Kidney Diseases, vol. 38, no. 6, supplement 6, pp. S25–S35, 2001.
[6]
Y. M. Di, C. G. Li, C. C. Xue, and S. Zhou, “Clinical drugs that interact with St. John's wort and implication in drug development,” Current Pharmaceutical Design, vol. 14, no. 17, pp. 1723–1742, 2008.
[7]
J. M. Wentworth, M. Agostini, J. Love, J. W. Schwabe, and V. K. K. Chatterjee, “St John's wort, a herbal antidepressant, activates the steroid X receptor,” Journal of Endocrinology, vol. 166, no. 3, pp. R11–R16, 2000.
[8]
S. Bauer, E. St？rmer, A. Johne et al., “Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients,” British Journal of Clinical Pharmacology, vol. 55, no. 2, pp. 203–211, 2003.
[9]
G. W. Barone, B. J. Gurley, B. L. Ketel, and S. R. Abul-Ezz, “Herbal supplements: a potential for drug interactions in transplant recipients,” Transplantation, vol. 71, no. 2, pp. 239–241, 2001.
[10]
C. Moschella and B. L. Jaber, “Interaction between cyclosporine and Hypericum perforatum (St. John's Wort) after organ transplantation,” American Journal of Kidney Diseases, vol. 38, no. 5, pp. 1105–1107, 2001.
[11]
D. G. Bailey, J. D. Spence, B. Edgar, C. D. Bayliff, and J. M. O. Arnold, “Ethanol enhances the hemodynamic effects of felodipine,” Clinical and Investigative Medicine, vol. 12, no. 6, pp. 357–362, 1989.
[12]
P. Schmiedlin-Ren, D. J. Edwards, M. E. Fitzsimmons et al., “Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents: decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins,” Drug Metabolism and Disposition, vol. 25, no. 11, pp. 1228–1233, 1997.
[13]
M. P. Ducharme, L. H. Warbasse, and D. J. Edwards, “Disposition of intravenous and oral cyclosporine after administration with grapefruit juice,” Clinical Pharmacology and Therapeutics, vol. 57, no. 5, pp. 485–491, 1995.
[14]
L. L. Ioannides-Demos, N. Christophidis, P. Ryan, P. Angelis, L. Liolios, and A. J. McLean, “Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases,” Journal of Rheumatology, vol. 24, no. 1, pp. 49–54, 1997.
[15]
G. C. Yee, D. L. Stanley, L. J. Pessa et al., “Effect of grapefruit juice on blood cyclosporin concentration,” The Lancet, vol. 345, no. 8955, pp. 955–956, 1995.
[16]
D. I. Min, Y. Ku, P. J. Perry et al., “Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients,” Transplantation, vol. 62, no. 1, pp. 123–125, 1996.
[17]
L. J. Brunner, K. Pai, M. Y. Munar, M. B. Lande, A. J. Olyaei, and J. A. Mowry, “Effect of grapefruit juice on cyclosporin A pharmacokinetics in pediatric renal transplant patients,” Pediatric Transplantation, vol. 4, no. 4, pp. 313–321, 2000.
[18]
H. Chiang, P. L. Chao, S. Hsiu, K. Wen, S. Tsai, and Y. Hou, “Ginger significantly decreased the oral bioavailability of cyclosporine in rats,” American Journal of Chinese Medicine, vol. 34, no. 5, pp. 845–855, 2006.
[19]
A. W. Zuardi, “Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action,” Revista Brasileira de Psiquiatria, vol. 30, no. 3, pp. 271–280, 2008.
[20]
W. Jaeger, L. Z. Benet, and L. M. Bornheim, “Inhibition of cyclosporine and tetrahydrocannabinol metabolism by cannabidiol in mouse and human microsomes,” Xenobiotica, vol. 26, no. 3, pp. 275–284, 1996.
[21]
J. W. Budzinski, B. C. Foster, S. Vandenhoek, and J. T. Arnason, “An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures,” Phytomedicine, vol. 7, no. 4, pp. 273–282, 2000.
[22]
L. H. Goldstein, M. Elias, G. Ron-Avraham et al., “Consumption of herbal remedies and dietary supplements amongst patients hospitalized in medical wards,” British Journal of Clinical Pharmacology, vol. 64, no. 3, pp. 373–380, 2007.
[23]
R. Nowack and B. Nowak, “Herbal teas interfere with cyclosporin levels in renal transplant patients,” Nephrology Dialysis Transplantation, vol. 20, no. 11, pp. 2554–2556, 2005.
[24]
Y. C. Hou, S. P. Lin, and P. D. Chao, “Liquorice reduced cyclosporine bioavailability by activating P-glycoprotein and CYP 3A,” Food Chemistry, vol. 135, no. 4, pp. 2307–2312, 2012.
[25]
B. Huang, G. Li, F. Ren et al., “Effect of Glycyrrhiza inflata and Daphne genkwa on permeabilities of rhodamine 123, a P-glycoprotein substrate across rat jejunum membranes in vitro,” Zhongguo Zhongyao Zazhi, vol. 33, no. 21, pp. 2521–2526, 2008.
[26]
N. Yoshida, M. Koizumi, I. Adachi, and J. Kawakami, “Inhibition of P-glycoprotein-mediated transport by terpenoids contained in herbal medicines and natural products,” Food and Chemical Toxicology, vol. 44, no. 12, pp. 2033–2039, 2006.
[27]
M. Lai, S. Hsiu, Y. Hou, S. Tsai, and P. L. Chao, “Significant decrease of cyclosporine bioavailability in rats caused by a decoction of the roots of Scutellaria baicalensis,” Planta Medica, vol. 70, no. 2, pp. 132–137, 2004.
[28]
Y. Wang, P. L. Chao, S. Hsiu, K. Wen, and Y. Hou, “Lethal quercetin-digoxin interaction in pigs,” Life Sciences, vol. 74, no. 10, pp. 1191–1197, 2004.
[29]
C. Y. Yang, P. D. L. Chao, Y. C. Hou, S. Y. Tsai, K. C. Wen, and S. L. Hsiu, “Marked decrease of cyclosporin bioavailability caused by coadministration of ginkgo and onion in rats,” Food and Chemical Toxicology, vol. 44, no. 9, pp. 1572–1578, 2006.
[30]
S. Hsiu, Y. Hou, Y. Wang, C. Tsao, S. Su, and P. L. Chao, “Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats,” Life Sciences, vol. 72, no. 3, pp. 227–235, 2002.
[31]
C. Yu, P. Wu, Y. Hou et al., “Quercetin and rutin reduced the bioavailability of cyclosporine from Neoral, an immunosuppressant, through activating P-glycoprotein and CYP 3A4,” Journal of Agricultural and Food Chemistry, vol. 59, no. 9, pp. 4644–4648, 2011.
[32]
S. H. Yale and I. Glurich, “Analysis of the inhibitory potential of Ginkgo biloba, Echinacea purpurea, and Serenoa repens on the metabolic activity of cytochrome P450 3A4, 2D6, and 2C9,” Journal of Alternative and Complementary Medicine, vol. 11, no. 3, pp. 433–439, 2005.
[33]
P. W. Hsu, C. S. Shia, S. P. Lin, et al., “Potential risk of mulberry-drug interaction: modulation on P-glycoprotein and cytochrome P450 3A,” Journal of Agricultural and Food Chemistry, vol. 61, no. 18, pp. 4464–4469, 2013.
[34]
Z. Mostafavi-pour, F. Zal, A. Monabati, and M. Vessal, “Protective effects of a combination of quercetin and vitamin E against cyclosporine A-induced oxidative stress and hepatotoxicity in rats,” Hepatology Research, vol. 38, no. 4, pp. 385–392, 2008.
[35]
F. Zal, Z. Mostafavi-Pour, and M. Vessal, “Comparison of the effects of vitamin E and/or quercetin in attenuating chronic cyclosporine A-induced nephrotoxicity in male rats,” Clinical and Experimental Pharmacology and Physiology, vol. 34, no. 8, pp. 720–724, 2007.
[36]
P. S. V. Satyanarayana, D. Singh, and K. Chopra, “Quercetin, a bioflavonoid, protects against oxidative stress-related renal dysfunction by cyclosporine in rats,” Methods and Findings in Experimental and Clinical Pharmacology, vol. 23, no. 4, pp. 175–181, 2001.
[37]
G. Regev-Shoshani, O. Shoseyov, and Z. Kerem, “Influence of lipophilicity on the interactions of hydroxy stilbenes with cytochrome P450 3A4,” Biochemical and Biophysical Research Communications, vol. 323, no. 2, pp. 668–673, 2004.
[38]
L. Yu, S. Wu, M. Zhang, and C. Pan, “Effect of resveratrol alone and its combination with cyclosporin A on the immune function of human peripheral blood T lymphocytes,” Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, vol. 19, no. 6, pp. 549–551, 2003.
[39]
V. Chander, N. Tirkey, and K. Chopra, “Resveratrol, a polyphenolic phytoalexin protects against cyclosporine-induced nephrotoxicity through nitric oxide dependent mechanism,” Toxicology, vol. 210, no. 1, pp. 55–64, 2005.
[40]
S. Yang, S. Tsai, Y. Hou, and P. L. Chao, “Inductive modulation on P-glycoprotein and cytochrome 3A by resveratrol, a constituent of grapes,” Food Chemistry, vol. 133, no. 3, pp. 683–688, 2012.
[41]
J. Tacklind, R. MacDonald, I. Rutks, and T. J. Wilt, “Serenoa repens for benign prostatic hyperplasia,” Cochrane Database of Systematic Reviews, no. 12, Article ID CD001423, 2012.
[42]
J. S. Markowitz, J. L. Donovan, C. L. DeVane et al., “Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers,” Clinical Pharmacology and Therapeutics, vol. 74, no. 6, pp. 536–542, 2003.
[43]
J. C. Gorski, S. Huang, A. Pinto et al., “The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo,” Clinical Pharmacology and Therapeutics, vol. 75, no. 1, pp. 89–100, 2004.
[44]
B. J. Gurley, S. F. Gardner, M. A. Hubbard, D. K. Williams, W. B. Gentry, and J. Carrier, “In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto,” Clinical Pharmacology and Therapeutics, vol. 76, no. 5, pp. 428–440, 2004.
[45]
H.-W. Xin, X.-C. Wu, Q. Li, A.-R. Yu, M.-Y. Zhong, and Y.-Y. Liu, “The effects of berberine on the pharmacokinetics of ciclosporin A in healthy volunteers,” Methods and Findings in Experimental and Clinical Pharmacology, vol. 28, no. 1, pp. 25–29, 2006.
[46]
X. Wu, Q. Li, H. Xin, A. Yu, and M. Zhong, “Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study,” European Journal of Clinical Pharmacology, vol. 61, no. 8, pp. 567–572, 2005.
[47]
G. Pan, G. Wang, X. Liu, J. P. Fawcett, and Y. Xie, “The involvement of P-glycoprotein in berberine absorption,” Pharmacology and Toxicology, vol. 91, no. 4, pp. 193–197, 2002.
[48]
W. Qiu, X. H. Jiang, C. X. Liu, Y. Ju, and J. X. Jin, “Effect of berberine on the pharmacokinetics of substrates of CYP3A and P-gp,” Phytotherapy Research, vol. 23, no. 11, pp. 1553–1558, 2009.
[49]
P. Tsai and T. Tsai, “Hepatobiliary excretion of berberine,” Drug Metabolism and Disposition, vol. 32, no. 4, pp. 405–412, 2004.
