Planta Med 2009; 75(11): 1196-1202
DOI: 10.1055/s-0029-1185534
Pharmacology
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Toxicological and Pharmacokinetic Evaluation of Concomitant Intake of Grapefruit Juice and Simvastatin in Rats after Repeated Treatment over 28 Days

Veronika Butterweck1 , Immo Zdrojewski1 , Cheryl Galloway2 , Reginald Frye2 , Hartmut Derendorf1
  • 1College of Pharmacy, Department of Pharmaceutics, University of Florida, Gainesville, FL, USA
  • 2College of Pharmacy, Department of Pharmacy Practice, University of Florida, Gainesville, FL, USA
Weitere Informationen

Publikationsverlauf

received October 17, 2008 revised January 26, 2009

accepted February 25, 2009

Publikationsdatum:
06. April 2009 (online)

Abstract

Since data concerning the toxicity and pharmacokinetics of concomitant repeated administration of grapefruit juice (GFJ) and simvastatin are lacking, we performed a chronic study in rats over a 4-week period using two different strengths (regular [RS] and double strength [DS]) of GFJ and two different doses of simvastatin (20 and 80 mg/kg, respectively). Both juices did not have a significant effect on the pharmacokinetic parameters of either simvastatin lactone (SVL) or its active metabolite simvastatin hydroxy acid (SVA) when administered concomitantly in a dose of 20 mg/kg over 28 days. However, when administered with 80 mg/kg simvastatin concentrations were elevated up to the last day of the study with DS‐GFJ and to a lesser extent with RS‐GFJ. Evaluation of toxicological parameters revealed a significant decrease in body and liver weights in groups receiving 20 mg/kg or 80 mg/kg simvastatin alone as well as in groups receiving simvastatin concomitantly with either DS- or RS‐GFJ. No significant differences were detected for alanine (ALT) and aspartate (AST) aminotranferases in all groups. Chronic treatment with simvastatin significantly decreased plasma cholesterol levels (18 % for 20 mg/kg, 19 % for 80 mg/kg, respectively) as did coadministration of 80 mg/kg simvastatin with either RS‐GFJ or DS‐GFJ (33 %, 16 %). Interestingly, treatment with RS- or DS‐GFJ alone significantly decreased plasma cholesterol levels by 22 % and 30 %, respectively. In conclusion, our results suggest that toxic effects in rats of concomitant intake of simvastatin and GFJ over 28 days are not more pronounced than those of simvastatin alone and that dose relationships between the administration of the juice and the drug may be important in determining the magnitude of the interaction.

References

  • 1 Bailey D G, Spence J D, Edgar B, Bayliff C D, Arnold J M. Ethanol enhances the hemodynamic effects of felodipine.  Clin Invest Med. 1989;  12 357-362
  • 2 Schmiedlin-Ren P, Edwards D J, Fitzsimmons M E, He K, Lown K S, Woster P M, Rahman A, Thummel K E, Fisher J M, Hollenberg P F, Watkins P B. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins.  Drug Metab Dispos. 1997;  25 1228-1233
  • 3 Romiti N, Tramonti G, Donati A, Chieli E. Effects of grapefruit juice on the multidrug transporter P-glycoprotein in the human proximal tubular cell line HK‐2.  Life Sci. 2004;  76 293-302
  • 4 Fuhr U, Maier-Bruggemann A, Blume H, Muck W, Unger S, Kuhlmann J, Huschka C, Zaigler M, Rietbrock S, Staib A H. Grapefruit juice increases oral nimodipine bioavailability.  Int J Clin Pharmacol Ther. 1998;  36 126-132
  • 5 Dresser G K, Spence J D, Bailey D G. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition.  Clin Pharmacokinet. 2000;  38 41-57
  • 6 Lilja J J, Kivisto K T, Neuvonen P J. Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG‐CoA reductase inhibitors.  Clin Pharmacol Ther. 1998;  64 477-483
  • 7 Lilja J J, Neuvonen M, Neuvonen P J. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin.  Br J Clin Pharmacol. 2004;  58 56-60
  • 8 Bailey D G, Dresser G K, Kreeft J H, Munoz C, Freeman D J, Bend J R. Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients.  Clin Pharmacol Ther. 2000;  68 468-477
  • 9 Lane H Y, Jann M W, Chang Y C, Chiu C C, Huang M C, Lee S H, Chang W H. Repeated ingestion of grapefruit juice does not alter clozapine's steady-state plasma levels, effectiveness, and tolerability.  J Clin Psychiatry. 2001;  62 812-817
  • 10 Mangano N G, Cutuli V M, Caruso A, De Bernardis E, Amico-Roxas M. Grapefruit juice effects on the bioavailability of cyclosporin-A in rats.  Eur Rev Med Pharmacol Sci. 2001;  5 1-6
  • 11 De Castro W V, Mertens-Talcott S, Rubner A, Butterweck V, Derendorf H. Variation of flavonoids and furanocoumarins in grapefruit juices: a potential source of variability in grapefruit juice-drug interaction studies.  J Agric Food Chem. 2006;  54 249-255
  • 12 Vickers S, Duncan C A, Vyas K P, Kari P H, Arison B, Prakash S R, Ramjit H G, Pitzenberger S M, Stokker G, Duggan D E. In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase.  Drug Metab Dispos. 1990;  18 476-483
  • 13 Westwood F R, Bigley A, Randall K, Marsden A M, Scott R C. Statin-induced muscle necrosis in the rat: distribution, development, and fibre selectivity.  Toxicol Pathol. 2005;  33 246-257
  • 14 Bernini G P, Argenio G F, Gasperi M, Vivaldi M S, Franchi F, Salvetti A. Effects of long-term simvastatin treatment on testicular and adrenal steroidogenesis in hypercholesterolemic patients.  J Endocrinol Invest. 1994;  17 227-233
  • 15 Wang Q, Tang X N, Wang L, Yenari M A, Ying W, Goh B C, Lee H S, Wilder-Smith E P, Wong P T. Effects of high dose of simvastatin on levels of dopamine and its reuptake in prefrontal cortex and striatum among SD rats.  Neurosci Lett. 2006;  408 189-193
  • 16 Banfield C, Gupta S, Marino M, Lim J, Affrime M. Grapefruit juice reduces the oral bioavailability of fexofenadine but not desloratadine.  Clin Pharmacokinet. 2002;  41 311-318
  • 17 Kantola T, Kivisto K T, Neuvonen P J. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid.  Clin Pharmacol Ther. 1998;  63 397-402
  • 18 Uno T, Ohkubo T, Motomura S, Sugawara K. Effect of grapefruit juice on the disposition of manidipine enantiomers in healthy subjects.  Br J Clin Pharmacol. 2006;  61 533-537
  • 19 Yasui N, Kondo T, Suzuki A, Otani K, Mihara K, Furukori H, Kaneko S, Inoue Y. Lack of significant pharmacokinetic interaction between haloperidol and grapefruit juice.  Int Clin Psychopharmacol. 1999;  14 113-118
  • 20 Ando H, Tsuruoka S, Yanagihara H, Sugimoto K, Miyata M, Yamazoe Y, Takamura T, Kaneko S, Fujimura A. Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin.  Br J Clin Pharmacol. 2005;  60 494-497
  • 21 Fukazawa I, Uchida N, Uchida E, Yasuhara H. Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese.  Br J Clin Pharmacol. 2004;  57 448-455
  • 22 Rogers J D, Zhao J, Liu L, Amin R D, Gagliano K D, Porras A G, Blum R A, Wilson M F, Stepanavage M, Vega J M. Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.  Clin Pharmacol Ther. 1999;  66 358-366
  • 23 Rochling F A. Evaluation of abnormal liver tests.  Clin Cornerstone. 2001;  3 1-12
  • 24 Dale K M, White C M, Henyan N N, Kluger J, Coleman C I. Impact of statin dosing intensity on transaminase and creatine kinase.  Am J Med. 2007;  120 706-712
  • 25 Gorinstein S, Caspi A, Libman I, Lerner H T, Huang D, Leontowicz H, Leontowicz M, Tashma Z, Katrich E, Feng S, Trakhtenberg S. Red grapefruit positively influences serum triglyceride level in patients suffering from coronary atherosclerosis: studies in vitro and in humans.  J Agric Food Chem. 2006;  54 1887-1892
  • 26 Gorinstein S, Caspi A, Libman I, Katrich E, Lerner H T, Trakhtenberg S. Fresh Israeli jaffa sweetie juice consumption improves lipid metabolism and increases antioxidant capacity in hypercholesterolemic patients suffering from coronary artery disease: studies in vitro and in humans and positive changes in albumin and fibrinogen fractions.  J Agric Food Chem. 2004;  52 5215-5222
  • 27 Borradaile N M, de Dreu L E, Barrett P H, Huff M W. Inhibition of hepatocyte apoB secretion by naringenin: enhanced rapid intracellular degradation independent of reduced microsomal cholesteryl esters.  J Lipid Res. 2002;  43 1544-1554
  • 28 Shin Y W, Bok S H, Jeong T S, Bae K H, Jeoung N H, Choi M S, Lee S H, Park Y B. Hypocholesterolemic effect of naringin associated with hepatic cholesterol regulating enzyme changes in rats.  Int J Vitam Nutr Res. 1999;  69 341-347
  • 29 Smith P F, Eydelloth R S, Grossman S J, Stubbs R J, Schwartz M S, Germershausen J I, MacDonald J S. Myopathy associated with HMG‐CoA reductase inhibitors (HMGRIs) and cyclosporin A: evaluation in a rat model.  Eur Heart J. 1992;  13 (Suppl B) 2-6
  • 30 Tobert J A, Shear C L, Chremos A N, Mantell G E. Clinical experience with lovastatin.  Am J Cardiol. 1990;  65 23F-26F
  • 31 Reijneveld J C, Koot R W, Bredman J J, Joles J A, Bar P R. Differential effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on the development of myopathy in young rats.  Pediatr Res. 1996;  39 1028-1035

Dr. Veronika Butterweck

Department of Pharmaceutics
College of Pharmacy
University of Florida

PO Box 100494

Gainesville, FL 32610

USA

Telefon: + 1 35 22 73 78 59

eMail: butterwk@cop.ufl.edu