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. KHALIFA^1,4*

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

Received: 28 May 2020/Accepted: 7 August 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

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*Corresponding author; email: hazem.khalifa1@vet.kfs.edu.eg