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In the treatment of COVID-19, the antiviral medication Favipiravir has proven to be quite successful. Its metabolism is mediated by the enzymes aldehyde oxidase (AO) and xanthine oxidase (XO). This research investigated the potential drug-drug interaction between
favipiravir and amlodipine in hypertensive rabbits. Twenty local adult male rabbits (aged between 10 and 12 months and weighing between 2 and 2.5 kg) were induced with hypertension by 20 mg/kg BW of desoxycorticosterone acetate subcutaneously for three
weeks and then divided randomly into two groups of ten. The first group received a single oral dose of 40 mg/kg BW of favipiravir, while the second group received 5 mg/kg of amlodipine orally for 14 consecutive days to inhibit AO before receiving a single oral dose of 40 mg/kg BW of favipiravir. Blood samples were collected from the marginal ear vein at 15, 30, 45 min, and 1, 2, 4, 8, 12, 24, 48, 36, 48, and 72 h. High-performance liquid chromatography (HPLC) was used to determine the concentration of favipiravir in the
plasma. The results showed that co-administration of amlodipine prolonged the time taken for favipiravir (Tmax) to reach maximum plasma concentration (Cmax) and decreased its elimination half-life, while increasing the area under the curve (AUC). Amlodipine also
prolonged the elimination of favipiravir by reducing the clearance per unit time (Cl/f).
Additionally, hypertension potentiated the effect of amlodipine on the absorption, distribution, metabolism, and excretion of favipiravir. In conclusion, concomitant use of favipiravir with other drugs that affect AO enzyme activity may alter the pharmacokinetic
profile of the drug. Therefore, adjusting the dose of favipiravir administered to hypertensive patients receiving amlodipine is recommended.
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Subramanian A, Adhimoolam M, Kannan S. Study of drug-Drug
interactions among the hypertensive patients in a tertiary care
teaching hospital. Perspect Clin Res. 2018;9(1):9-14.
Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad
spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys
Biol Sci 2017;93(7):449-63.
Hamza RZ, Al-Talhi T, Gobouri AA, Alsanie WF, El-Megharbel SM. Are
favipiravir and acyclovir with IgG injections supplemented with
vitamin D “suggested therapeutic option” can fight against COVID-19.
Adv. Anim. Vet. Sci. 2021;9(4):549-554.
Singh TU, Parida S, Lingaraju MC, Kesavan M, Kumar D, Singh RK.
Drug repurposing approach to fight COVID-19. Pharmacol Rep.
Kumar D, Trivedi N. Disease-drug and drug-drug interaction in
COVID-19: Risk and assessment. Biomed Pharmacother.
James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C,
Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O,
Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva
AS, Ortiz E. 2014 evidence-based guideline for the management of
high blood pressure in adults: report from the panel members
appointed to the Eighth Joint National Committee (JNC 8). JAMA.
Sivva D, Mateti UV, Neerati VM, Thiruthopu NS, Martha S. Assessment
of drug-drug interactions in hypertensive patients at a
superspeciality hospital. Avicenna J Med. 2015;5(02):29-35.
Shirley M, McCormack PL. Perindopril/amlodipine (Prestalia®): a
review in hypertension. Am J Cardio Dru. 2015;15(5):363-370.
Rodriguez F, Solomon N, de Lemos JA, Das SR, Morrow DA, Bradley
SM, et al. Racial and ethnic differences in presentation and outcomes
for patients hospitalized with COVID-19: findings from the American
Heart Association’s COVID-19 Cardiovascular Disease Registry.
Negru PA, Radu AF, Vesa CM, Behl T, Abdel-Daim MM, Nechifor AC, et
al. Therapeutic dilemmas in addressing SARS-CoV-2 infection:
Favipiravir versus Remdesivir. Biomed Pharmacother.
Ahmad RM, Ibrahim OM. Effect of erythromycin on pharmacokinetics
of Amlodipine in hypertensive rabbits. On. J Vet Res. 2019;23(6):555-
Harahap Y, Diptasaadya R, Purwanto DJ. Volumetric Absorptive
Microsampling as a Sampling Alternative in Clinical Trials and
Therapeutic Drug Monitoring During the COVID-19 Pandemic: A
Review. Drug Des Devel Ther. 2020;14:5757-5771.
Nair AB, Jacob S. A simple practice guide for dose conversion between
animals and human. J Basic Clin Pharm. 2016;7(2):27-31.
Bulduk I . Comparison of HPLC and UV Spectrophotometric Methods
for Quantification of Favipiravir in Pharmaceutical Formulations. Iran
J Pharm Res. 2021;20(3):57-65.
Zhang Y, Huo M, Zhou J, Xie S. PKSolver: An add-in program for
pharmacokinetic and pharmacodynamic data analysis in Microsoft
Excel. Comput Methods Programs Biomed. 2010;99(3):306-314.
SAS S. User's guide: statistics. SAS Institute Inc, Cary, NC. 1985;956.
Delyani JA, Rocha R, Cook CS, Tobert DS, Levin S, Roniker B, et al.
Eplerenone: a selective aldosterone receptor antagonist (SARA).
Cardiovasc Drug Rev. 2001;19(3):185-200.
Yemane H, Busauskas M, Burris SK, Knuepfer MM. Neurohumoral
mechanisms in deoxycorticosterone acetate (DOCA)–salt
hypertension in rats. Exp Physiol. 2010;95(1):51-55.
Yang S, Lee YS, Oh E. Pharmacokinetics of drugs in spontaneously or
secondary hypertensive rats. Xenobiotica. 2014;44(1):77-88.
Wang D, Luo Y, Myakala K, Orlicky DJ, Dobrinskikh E, Wang X, et al.
Serelaxin improves cardiac and renal function in DOCA-salt
hypertensive rats. Sci Rep. 2017;7(1):9793.
Yan H, Valdes AM, Vijay A, Wang S, Liang L, Yang S, et al. Role of drugs
used for chronic disease management on susceptibility and severity
of COVID-19: a large case-control study. Clin Pharmacol
O zek DA, Keski̇n Z, Hande Y, Tu rkmen NB, Aslan S, U nu var S. Drugdrug interaction of aldehyde oxidase inhibitor and xanthine oxidase
inhibitor with favipiravir. Value Health Sci. 2022;12(3):511-519.
Deb S, Arrighi S. Potential effects of COVID-19 on cytochrome P450-
mediated drug metabolism and disposition in infected patients. Eur J
Drug Metab Pharmacokinet. 2021;46(2):185-203.
Madelain V, Nguyen TH, Olivo A, De Lamballerie X, Guedj J, Taburet
AM, et al. Ebola virus infection: review of the pharmacokinetic and
pharmacodynamic properties of drugs considered for testing in
human efficacy trials. Clin Pharmacokinet. 2016;55(8):907-923.
Du YX, Chen XP. Favipiravir: pharmacokinetics and concerns about
clinical trials for 2019-nCoV infection. Clin Pharmacol Ther.
Mishima E, Anzai N, Miyazaki M, Abe T. Uric acid elevation by
favipiravir, an antiviral drug. Tohoku J Exp Med. 2020;251(2):87-90.
Demir E, Su tcu og lu O, Demir B, U nsal O, Yazici O. A possible
interaction between favipiravir and methotrexate: Drug-induced
hepatotoxicity in a patient with osteosarcoma. J Oncol Pharm Pract.
Hanioka N, Saito K, Isobe T, Ohkawara S, Jinno H, Tanaka-Kagawa T.
Favipiravir biotransformation in liver cytosol: Species and sex
differences in humans, monkeys, rats, and mice. Biopharm Drug