Sains Malaysiana 50(3)(2021): 829-837

http://doi.org/10.17576/jsm-2021-5003-23

 

Comparative Evaluation of the Effects of Atorvastatin and Lovastatin on the Pharmacokinetics of Aliskiren in Rats

(Penilaian Perbandingan Kesan Atorvastatin dan Lovastatin terhadap Farmakokinetik Aliskiren pada Tikus)

 

AMAL SHARAF1, KAMAL A. EL-SHAZLY1, AMERA ABD EL LATIF1, KHALED S. ABDELKAWY2, FAWZY ELBARBRY3 & HAZIM O. KHALIFA1,4*

 

1Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh, 33516 Egypt

 

2Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, 33516 Egypt

 

3School of Pharmacy, Pacific University, Hillsboro OR, 97123 USA

 

4Department of Infectious Diseases, Graduate School of Medicine, International University of Health and Welfare, Narita 286-8686, Japan

 

Diserahkan: 28 Mei 2020/Diterima: 7 Ogos 2020

 

ABSTRACT

The worldwide increase in the number patients with high blood pressure poses serious clinical challenges. Little is known regarding the interactions between the various drugs used to treat heart diseases. The present study evaluates and compares the effects of administration of multiple doses of atorvastatin or lovastatin on the pharmacokinetics of aliskiren in rats in an effort to determine their underlying mechanisms. A total of 90 healthy female albino rats were randomly divided into three groups. All groups were treated with aliskiren by oral gavage at 8.57 mg/kg daily for 14 days. In addition to aliskiren, group 2 received atorvastatin at a dose of 1.143 mg/kg for 7 days. In addition to aliskiren, group 3 received lovastatin at a dose of 1.143 mg/kg for 7 days. After blood samples were collected at specific time intervals, aliskiren concentrations were determined using liquid chromatography-tandem mass spectrometry. Relative to the control treatment, atorvastatin treatment resulted in non-significant alterations in the pharmacokinetic parameters of aliskiren. In contrast, lovastatin resulted in a significant increase in the area under the curve, peak plasma concentration, and elimination half-life by 21, 10, and 72%, respectively. Additionally, lovastatin significantly reduced oral clearance by 23%. Inhibition of aliskiren metabolism via the hepatic CYP3A subfamily and/or inhibition of intestinal P-glycoprotein and/or the CYP3A subfamily was identified as a possible mechanism. This study is the first to report that only lovastatin causes a marked increase in aliskiren bioavailability. Caution should be taken when lovastatin and aliskiren are administrated concomitantly in clinical practice.

 

Keywords: Coronary artery disease; drug interactions; high blood pressure; statins

 

ABSTRAK

Peningkatan jumlah pesakit darah tinggi di seluruh dunia menimbulkan cabaran klinikal yang serius. Tidak banyak yang diketahui mengenai interaksi antara pelbagai dadah yang digunakan untuk merawat penyakit jantung. Kajian ini menilai dan membandingkan kesan pemberian pelbagai dos atorvastatin atau lovastatin terhadap farmakokinetik aliskiren pada tikus dalam usaha untuk menentukan mekanisme asasnya. Sebanyak 90 tikus albino betina yang sihat dibahagikan secara rawak kepada tiga kumpulan. Semua kumpulan dirawat dengan aliskiren dengan pemberian oral sebanyak 8.57 mg/kg setiap hari selama 14 hari. Sebagai tambahan kepada aliskiren, kumpulan 2 menerima atorvastatin pada dos 1.143 mg/kg selama 7 hari. Sebagai tambahan kepada aliskiren, kumpulan 3 menerima lovastatin pada dos 1.143 mg/kg selama 7 hari. Setelah sampel darah dikumpulkan pada selang waktu tertentu, kepekatan aliskiren ditentukan menggunakan spektrometri jisim kromatografi cair-tandem. Berkaitan dengan rawatan kawalan, rawatan atorvastatin mengakibatkan perubahan yang tidak ketara pada parameter farmakokinetik aliskiren. Sebaliknya, lovastatin menghasilkan peningkatan yang signifikan di kawasan di bawah kurva, kepekatan plasma puncak dan penghilangan separuh hayat masing-masing sebanyak 10, 21 dan 72%. Selain itu, lovastatin mengurangkan pelepasan oral dengan ketara sebanyak 23%. Sebaliknya, lovastatin menghasilkan peningkatan yang signifikan di kawasan di bawah kurva, kepekatan plasma puncak, dan penghilangan separuh hayat masing-masing sebanyak 21, 10 dan 72%. Selain itu, lovastatin mengurangkan pelepasan oral dengan ketara sebanyak 23%. Perencatan metabolisme aliskiren melalui subfamili CYP3A hepatik dan/atau perencatan P-glikoprotein usus dan/atau subfamili CYP3A dikenal pasti sebagai mekanisme yang berkemungkinan. Kajian ini adalah yang pertama melaporkan bahawa hanya lovastatin yang menyebabkan peningkatan bioavailabiliti aliskiren yang ketara. Perhatian harus diambil ketika lovastatin dan aliskiren diberikan bersamaan dalam praktik klinikal.

 

Kata kunci: Interaksi dadah; penyakit arteri koronari; statin; tekanan darah tinggi

 

RUJUKAN

Abbasi, M., Valizadeh, H., Ham-ishekar, H., Amirkhiz, M.B. & Milani, P.Z. 2016. In vitro and in situ effects of atorvastatin and ezetimibe on P-glycoprotein expression and function. Bangladesh Journal of Pharmacology 11(4): 911-919.

Abdelkawy, K.S., Donia, A.M., Turner, R.B. & Elbarbry, F. 2016. Effects of lemon and seville orange juices on the pharmacokinetic properties of sildenafil in healthy subjects. Drugs in R&D 16(3): 271-278.

Ballantyne, C.M., Corsini, A., Davidson, M.H., Holdaas, H., Jacobson, T.A., Leitersdorf, E., März, W., Reckless, J.P. & Stein, E.A. 2003. Risk for myopathy with statin therapy in high-risk patients. Archives of Internal Medicine 163(5): 553-564.

Benjamin, E.J., Blaha, M.J., Chiuve, S.E., Cushman, M., Das, S.R., Deo, R., de Ferranti, S.D., Floyd, J., Fornage, M., Gillespie, C., Isasi, C.R., Jiménez, M.C., Jordan, L.C., Judd, S.E., Lackland, D., Lichtman, J.H., Lisabeth, L., Liu, S., Longenecker, C.T., Mackey, R.H., Matsushita, K., Mozaffarian, D., Mussolino, M.E., Nasir, K., Neumar, R.W., Palaniappan, L., Pandey, D.K., Thiagarajan, R.R., Reeves, M.J., Ritchey, M., Rodriguez, C.J., Roth, G.A., Rosamond, W.D., Sasson, C., Towfighi, A., Tsao, C.W., Turner, M.B., Virani, S.S., Voeks, J.H., Willey, J.Z., Wilkins, J.T., Wu, J.H., Alger, H.M., Wong, S.S., Muntner, P. & American Heart Association Statistics Committee and Stroke Statistics Subcommittee. 2017. Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation 135(10): e146-e603.

Bizukojc, M. & Ledakowicz, S. 2007. A macrokinetic modelling of the biosynthesis of lovastatin by Aspergillus terreus. Journal of Biotechnology 130(4): 422-435.

Blonk, M., van Beek, M., Colbers, A., Schouwenberg, B. & Burger, D. 2015. Pharmacokinetic drug-drug interaction study between raltegravir and atorvastatin 20 mg in healthy volunteers. Journal of Acquired Immune Deficiency Syndromes 69(1): 44-51.

Burckhardt, B.B., Ramusovic, S., Tins, J. & Laeer, S. 2013. Determination of aliskiren in human serum quantities by HPLC-tandem mass spectrometry appropriate for pediatric trials. Biomedical Chromatography: BMC 27(4): 477-486.

Choi, D.H., Chung, J.H. & Choi, J.S. 2010. Pharmacokinetic interaction between oral lovastatin and verapamil in healthy subjects: Role of P-glycoprotein inhibition by lovastatin. European Journal of Clinical Pharmacology 66(3): 285-290.

Chung, J.W., Yang, S.H. & Choi, J.S. 2010. Effects of lovastatin on the pharmacokinetics of nicardipine in rats. Biopharmaceutics and Drug Disposition 31(7): 436-441.

Ebert, U., Oertel, R. & Kirch, W. 2000. Influence of grapefruit juice on scopolamine pharmacokinetics and pharmacodynamics in healthy male and female subjects. International Journal of Clinical Pharmacology and Therapeutics 38(11): 523-531.

El-Sisi, A.A., Hegazy, S.K., Salem, K.A. & AbdElkawy, K.S. 2013. Atorvastatin improves erectile dysfunction in patients initially irresponsive to sildenafil by the activation of endothelial nitric oxide synthase. International Journal of Impotence Research 25(4): 143-148.

Foley-Comer, A.J., Young, A.M., Russell-Yarde, F. & Jordan, P. 2011. Aleglitazar, a balanced PPARα/γ agonist, has no clinically relevant pharmacokinetic interaction with high-dose atorvastatin or rosuvastatin. Expert Opinion on Investigational Drugs 20(1): 3-12.

Guo, Y., Zeng, J., Li, Q., Li, P., Luo, F.M., Zhang, W.Z., Lu, Y.X., Wang, Q., Zhang, W., Zeng, Z.P. & Liu, L.S. 2020. Preliminary clinical study of direct renin inhibitor aliskiren in the treatment of severe COVID-19 patients with hypertension. Zhonghua Nei Ke Za Zhi 59: E011.

Hong, S.P., Yang, J.S., Han, J.Y., Ha, S.I., Chung, J.W., Koh, Y.Y., Chang, K.S. & Choi, D.H. 2011. Effects of lovastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats: possible role of cytochrome P450 3A4 and P-glycoprotein inhibition by lovastatin. Journal of Pharmacy and Pharmacology 63(1): 129-135.

Hong, S.P., Chang, K.S., Koh, Y.Y., Choi, D.H. & Choi, J.S. 2009. Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite, norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin. Archives of Pharmacal Research 32(10): 1447-1452.

Hong, S.P., Chang, K.S., Choi, D.H. & Choi, J.S. 2007. Effect of atorvastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats. Archives of Pharmacal Research 30(1): 90-95.

Hulskotte, E.G., Feng, H.P., Xuan, F., Gupta, S., van Zutven, M.G., O’Mara, E., Wagner, J.A. & Butterton, J.R. 2013. Pharmacokinetic evaluation of the interaction between hepatitis C virus protease inhibitor Boceprevir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and pravastatin. Antimicrobial Agents and Chemotherapy 57(6): 2582-2588.

Jacobsen, W., Kuhn, B., Soldner, A., Kirchner, G., Sewing, K.F., Kollman, P.A., Benet, L.Z. & Christians, U. 2000. Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. Drug Metabolism and Disposition: The Biological Fate of Chemicals 28(11): 1369-1378.

Kashihara, Y., Ieiri, I., Yoshikado, T., Maeda, K., Fukae, M., Kimura, M., Hirota, T., Matsuki, S., Irie, S., Izumi, N., Kusuhara, H. & Sugiyama, Y. 2017. Small-dosing clinical study: Pharmacokinetic, pharmacogenomic (SLCO2B1 and ABCG2), and interaction (atorvastatin and grapefruit juice) profiles of 5 probes for OATP2B1 and BCRP. Journal of Pharmaceutical Sciences 106(9): 2688-2694.

Lee, C.K., Choi, J.S. & Choi, D.H. 2015. Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats: Possible role of P-gp and CYP3A4 inhibition by HMG-CoA reductase inhibitors. Pharmacological Reports 67(1): 44-51.

McKeand, W., Baird-Bellaire, S., Ermer, J. & Patat, A. 2018. A study of the potential interaction between Bazedoxifene and atorvastatin in healthy postmenopausal women. Clinical Pharmacology in Drug Development 7(8): 911-919.

Merai, R., Siegel, C., Rakotz, M., Basch, P., Wright, J., Wong, B., Thorpe, P.DHSc. & Thorpe, P. 2016. CDC grand rounds: A public health approach to detect and control hypertension. MMWR. Morbidity and Mortality Weekly Report 65(45): 1261-1264.

Mourad, J. & Levy, B.I. 2020. Interaction between RAAS inhibitors and ACE2 in the context of COVID-19. Nature Reviews Cardiology 17(5): 313-313.

Omar, A. 2020. Molecular docking reveals the potential of aliskiren, dipyridamole, mopidamol, rosuvastatin, rolitetracycline and metamizole to inhibit COVID-19 virus main protease. Chemrxiv. Preprint.

Pantzaris, N., Karanikolas, E., Tsiotsios, K. & Velissaris, D. 2017. Renin inhibition with aliskiren: A decade of clinical experience. Journal of Clinical Medicine 6(6): 61-80.

Patiño-Rodríguez, O., Torres-Roque, I., Martínez-Delgado, M., Escobedo-Moratilla, A. & Pérez-Urizar, J. 2014. Pharmacokinetic non-interaction analysis in a fixed-dose formulation in combination of atorvastatin and ezetimibe. Frontiers in Pharmacology 5(261): 1-9.

Pool, J.L. 2007. Direct renin inhibition: Focus on aliskiren. Journal of Managed Care Pharmacy 13(8)(Supp B): 21-33.

Prueksaritanont, T., Tang, C., Qiu, Y., Mu, L., Subramanian, R. & Lin, J.H. 2002. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metabolism and Disposition: The Biological Fate of Chemicals 30(11): 1280-1287.

Sakaeda, T., Fujino, H., Komoto, C., Kakumoto, M., Jin, J.S., Iwaki, K., Nishiguchi, K., Nakamura, T., Okamura, N. & Okumura, K. 2006. Effects of acid and lactone forms of eight HMG‐CoA Reductase Inhibitors on CYP‐mediated metabolism and MDR1‐mediated transport. Pharmaceutical Research 23(3): 506-512.

Sameer, E. 2019. Potentiation of cisplatin activity in colorectal cancer cells by lovastatin. Journal of Pharmaceutical Research International 28(1): 1-6.

Sarich, T.C., Schützer, K.M., Dorani, H., Wall, U., Kalies, I., Ohlsson, L. & Eriksson, U.G. 2004. No pharmacokinetic or pharmacodynamic interaction between atorvastatin and the oral direct thrombin inhibitor ximelagatran. Journal of Clinical Pharmacology 44(8): 928-934.

Saw, J., Steinhubl, S.R., Berger, P.B., Kereiakes, D.J., Serebruany, V.L., Brennan, D., Topol, E.J. & Clopidogrel for the Reduction of Events During Observation Investigators. 2003. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation 108(8): 921-924.

Struijker-Boudier, H. 2017. Should a statin be given to all hypertensive patients? Artery Research 18(C): 66-68.

Tapaninen, T., Backman, J.T., Kurkinen, K.J., Neuvonen, P.J. & Niemi, M. 2011. Itraconazole, a P-glycoprotein and CYP3A4 inhibitor, markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren. Journal of Clinical Pharmacology 51(3): 359-367.

Tod, M., Goutelle, S., Bleyzac, N. & Bourguignon, L. 2019. A generic model for quantitative prediction of interactions mediated by efflux transporters and cytochromes: Application to p-glycoprotein and cytochrome 3A4. Clinical Pharmacokinetics 58(4): 503-523.

Vaidyanathan, S., Jarugula, V., Dieterich, H.A., Howard, D. & Dole, W.P. 2008. Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clinical Pharmacokinetics 47(8): 515-531.

Vats, R., Varanasi, K.V., Arla, R., Veeraraghvan, S. & Rajak, S. 2012. Drug-drug interaction study to assess the effects of atorvastatin co-administration on pharmacokinetics and anti-thrombotic properties of cilostazol in male Wistar rats. Biopharmaceutics and Drug Disposition 33(8): 455-465.

Waldmeier, F., Glaenzel, U., Wirz, B., Oberer, L., Schmid, D., Seiberling, M., Valencia, J., Riviere, G.J., End, P. & Vaidyanathan, S. 2007. Absorption, distribution, metabolism, and elimination of the direct renin inhibitor aliskiren in healthy volunteers. Drug Metabolism and Disposition: The Biological Fate of Chemicals 35(8): 1418-1428.

Wang, Y., Jin, Y., Yun, X., Wang, M., Dai, Y. & Xia, Y. 2018. Co-administration with simvastatin or lovastatin alters the pharmacokinetic profile of sinomenine in rats through cytochrome P450-mediated pathways. Life Sciences 209: 228-235.

Wanitchanont, A., Somparn, P., Vadcharavivad, S., Chancharoenthana, W., Townamchai, N., Praditpornsilpa, K. & Avihingsanon, Y. 2014. Effects of atorvastatin on the pharmacokinetics of everolimus among kidney transplant recipients. Transplantation Proceedings 46(2): 418-421.

Wood, J.M., Maibaum, J., Rahuel, J., Grütter, M.G., Cohen, N.C., Rasetti, V., Rüger, H., Göschke, R., Stutz, S., Fuhrer, W., Schilling, W., Rigollier, P., Yamaguchi, Y., Cumin, F., Baum, H.P., Schnell, C.R., Herold, P., Mah, R., Jensen, C., O’Brien, E., Stanton, A. & Bedigian, M.P. 2003. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochemical and Biophysical Research Communications 308(4): 698-705.

Yoon, S.S., Carroll, M.D. & Fryar, C.D. 2015. Hypertension prevalence and control among adults: United States, 2011-2014. NCHS Data Brief 220: 1-8.

Zhao, C., Vaidyanathan, S., Yeh, C.M., Maboudian, M. & Armin Dieterich, H. 2006. Aliskiren exhibits similar pharmacokinetics in healthy volunteers and patients with Type 2 diabetes mellitus. Clinical Pharmacokinetics 45(11): 1125-1134.