Dilan AŞKIN ÖZEK, Zeliha KESKİN, Hande YÜCE, Neşe BAŞAK TÜRKMEN, Sümeyye ASLAN, Songül ÜNÜVAR

Aldehit Oksidaz İnhibitörü ve Ksantin Oksidaz İnhibitörünün Favipiravir ile İlaç-İlaç Etkileşimi

Amaç: Favipiravir, COVID-19 tedavisinde kullanılan etkili bir antiviraldir. Aldehit oksidaz (AO) ve ksantin oksidaz (KO) tarafından metabolize edilir. Bu çalışmada, favipiravir ile hem AO substratı hem de KO enzim inhibitörü allopurinol ve KO inhibitörü verapamil arasındaki ilaç-ilaç etkileşimleri araştırıldı. Gereç ve Yöntemler: 250-300 g ağırlığındaki 25 adet Sprague-Dawley dişi sıçan beş eşit gruba ayrıldı. İlaç uygulandıktan sonra 0, 15, 30, 45 dakika sonunda ve 1., 2., 4., 6. ve 8. saatlerin sonunda jugular venden kan örnekleri alındı. İlaç-kan konsantrasyonu, plazma kullanılarak HPLC-UV cihazında belirlendi. Sıçan karaciğer dokusunda AO ve KO enzim aktiviteleri ELISA yöntemi ile belirlendi. Bulgular: Allopurinol, favipiravirin Cmax'a (Tmax) ulaşması için geçen süreyi uzatmış, maksimum serum konsantrasyonunu (Cmax), eliminasyon yarı ömrünü (T1/2), eğrinin altındaki alanı (EAA) ve ortalama kalış süresini (MRT) azaltmıştır. Allopurinol, favipiravir ile birlikte uygulandığında birim zaman başına klirensi (Cl/f) önemli ölçüde azaltmıştır. Verapamil, favipiravirin eliminasyonunu hızlandırarak T1/2, MRT ve EAA'yı önemli ölçüde azaltmıştır. Favipiravir ise verapamil emilimini azalttı ve eliminasyonunu yavaşlattı. Verapamilin Cmax, EAA, Cl değerleri azaldı. Ayrıca T1/2, MRT ve dağılım hacmi (Vd) arttı. Sonuç: Sonuç olarak, favipiravirin AO ve/veya KO enzim aktivitelerini etkileyen diğer ilaçlarla birlikte kullanılması ilaçların farmakokinetik profillerinde ve ilaçları metabolize eden enzim düzeylerinde değişikliklere neden olabilir.

Anahtar Kelimeler:

Favipiravir, allopurinol, verapamil, farmakokinetik, aldehit oksidaz

Drug-Drug Interaction of Aldehyde Oxidase Inhibitor and Xanthine Oxidase Inhibitor with Favipiravir

Aim: Favipiravir is an effective antiviral used in the treatment of COVID-19. It is metabolized by aldehyde oxidase (AO) and xanthine oxidase (XO). This study investigated drug-drug interactions between favipiravir with both AO substrate and XO enzyme inhibitor, allopurinol, and an XO inhibitor, verapamil. Material and Methods: 25 Sprague-Dawley female rats, 250-300 g, were divided into five equal groups. Blood samples were taken from the jugular vein at the end of 0, 15, 30, and 45 minutes, and at the end of the 1st, 2nd, 4th, 6th, and 8th hours after the drugs were administered. The drug-blood concentration was determined in the HPLC-UV device using plasma. The ELISA method measured AO and XO enzyme activities in rat liver tissue. Results: Allopurinol prolonged the time taken for favipiravir to reach Cmax (Tmax), decreased maximum serum concentration (Cmax), elimination half-life (T1/2), area under the curve (AUC), and mean residence time (MRT). Allopurinol significantly reduced clearance per unit time (Cl/f) when co-administered with favipiravir. Verapamil accelerated the elimination of favipiravir, significantly reducing T1/2, MRT, and AUC. On the other hand, Favipiravir decreased the absorption of verapamil and slowed its elimination. Cmax, AUC, and Cl values of verapamil decreased. In addition, T1/2, MRT, and volume of distribution (Vd) increased. Conclusion: In conclusion, the concomitant use of favipiravir with other drugs that affect AO and/or XO enzyme activities may cause changes in the pharmacokinetic profiles of drugs and the levels of enzymes that metabolize drugs.

Keywords:

Favipiravir, allopurinol, verapamil, pharmacokinetics, aldehyde oxidase,

PDF

___

Baranovich T, Wong SS, Armstrong J, Marjuki H, Webby RJ, Webster RG, et al. T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J Virol. 2013; 87(7): 3741-51.
Kiso M, Takahashi K, Sakai-Tagawa Y, Shinya K, Sakabe S, Mai Le Quynh, et al. T-705 (favipiravir) activity against lethal H5N1 influenza A viruses. Proc Natl Acad Sci U S A. 2010; 107(2): 882-7.
Favipiravir 200 Mg Tablets Prospectus (Translated from Chinese), 24.03.2020.
Pharmaceuticals and Medical Devices Agency (PMDA). Report on the deliberation results: avigan. Japan; Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau. 2014; http://www.pmda.go.jp/files/000210319.pdf [Accessed: May 5, 2020].
Obach RS, Huynh P, Allen MC, Beedham C. Human liver aldehyde oxidase: inhibition by 239 drugs. J Clin Pharmacol. 2004; 44(1): 7-19.
Baldwin JJ, Kasinger PA, Novello FC, Sprague JM, Duggan DE. 4-Trifluoromethylimidazoles and 5-(4-pyridyl)-1,2,4-triazoles, new classes of xanthine oxidase inhibitors. J Med Chem. 1975; 18(9): 895-900.
Elion GB, Kovensky A, Hitchings GH. Metabolic studies of allopurinol, an inhibitor of xanthine oxidase. Biochem Pharmacol. 1966; 15(7): 863-80.
Bulduk İ. HPLC-UV method for quantification of favipiravir in pharmaceutical formulations. Acta Chromatogr. 2020; 33(3): 209-15.
Reinders MK, Nijdam LC, van Roon EN, Movig KL, Jansen TL, van de Laar MA, et al. A simple method for quantification of allopurinol and oxypurinol in human serum by high-performance liquid chromatography with UV-detection. J Pharm Biomed Anal. 2007; 45(2): 312-7.
He L, Wang S. Pharmacokonitic behavior and tissue distribution of verapamil and its enantiomers in rats by HPLC. Arch Pharm Res. 2003; 26(9): 763-7.
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
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): 907-23.
Demir E, Sütcüoğlu O, Demir B, Ünsal O, Yazıcı O. A possible interaction between favipiravir and methotrexate: Drug-induced hepatotoxicity in a patient with osteosarcoma. J Oncol Pharm Pract. 2022; 28(2): 445-8.
Du YX, Chen XP. Favipiravir: Pharmacokinetics and concerns about clinical trials for 2019-nCoV infection. Clin Pharmacol Ther. 2020; 108(2): 242-7.
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 Dispos. 2021; 42(5): 218-25.
Wang D, Hu B, Hu C. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020; 323(11): 1061-9.
Yue H, Bai X, Wang J, Yu Q, Liu W, Pu J, et al; Gansu Provincial Medical Treatment Expert Group of COVID-19. Clinical characteristics of coronavirus disease 2019 in Gansu province, China. Ann Palliat Med. 2020; 9(4): 1404-12.
Zhao Y, Harmatz JS, Epstein CR, Nakagawa Y, Kurosaki C, Nakamura T, et al. Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen. Br J Clin Pharmacol. 2015; 80(5): 1076-85.
Obach RS, Huynh P, Allen MC, Beedham C. Human liver aldehyde oxidase: inhibition by 239 drugs. J. Clin. Pharmacol. 2005; 44: 7-19.
Manevski N, King L, Pitt WR, Lecomte F, Toselli F. Metabolism by aldehyde oxidase: drug design and complementary approaches to challenges in drug discovery. J. Med. Chem. 2019; 62: 10955-94.
Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Report on the Deliberation Results [Internet] (2014).
Nguyen TH, Guedj J, Anglaret X, Laouenan C, Madelain V, Taburet AM, et al; JIKI study group. Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted. PLoS Negl Trop Dis. 2017; 11(2): e0005389.
Fujifilm Toyama Chemical Co., Ltd. (Fujifilm). (2019). The drug interview form of favipiravir (Avigan®). http://fftc.fujifilm.co.jp/med/abigan/pack/pdf/abigan_if_01.pdf)
Pharmaceuticals and Medical Devices Agency (PMDA). (2014). Report on the deliberation results: Avigan. http://www.pmda.go.jp/files/000210319.pdf)
Dalvie D, Di L. Aldehyde oxidase and its role as a drug metabolizing enzyme. Pharmacol Ther. 2019; 201: 137-80.
Gülhan R, Eryüksel E, Gülçebi İdriz Oğlu M, Çulpan Y, Toplu A, Kocakaya D, et al. Pharmacokinetic characterization of favipiravir in patients with COVID-19. Br J Clin Pharmacol. 2022; 88(7): 3516-22. https://doi.org/10.1111/bcp.15227.
Report on the Deliberation Results Avigan Tablet 200 mg by Pharmaceuticals and Medical Devices Agency (PMDA). Japan: Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare; 2014.
Avigan tablet 200 mg [package insert]. English translation by Toyama Chemical Co., Ltd; 2017.
Baker EH, Gnjidic D, Kirkpatrick CMJ, Pirmohamed M, Wright DFB, Zecharia AY. A call for the appropriate application of clinical pharmacological principles in the search for safe and efficacious COVID-19 (SARS-COV-2) treatments. Br J Clin Pharmacol. 2021; 87(3): 707-11.
Venisse N, Peytavin G, Bouchet S, Gagnieu MC, Garraffo R, Guilhaumou R, et al. Concerns about pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) studies in the new therapeutic area of COVID-19 infection. Antiviral Res. 2020; 181: 104866.