Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Research Article

Effect of Atorvastatin on Single Oral Pharmacokinetics and Safety of Daclatasvir in Rats: Emphasis on P-glycoprotein and Cytochrome P450

Author(s): Heba A. Elbadawy, Sara A. Wahdan and Ebtehal El-Demerdash*

Volume 23, Issue 6, 2022

Published on: 21 July, 2022

Page: [484 - 495] Pages: 12

DOI: 10.2174/1389200223666220404134524

Price: $65

Abstract

Objective: This study aimed to investigate the effect of atorvastatin on daclatasvir oral pharmacokinetics and safety and assess the possible underlining mechanisms by targeting P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4).

Methods: The transport of daclatasvir, as well as the standard rhodamine 123 by P-gp across the rat intestine, was studied in vitro using the non-everted sac method. To assess the pharmacokinetic profile of daclatasvir in vivo, rats were divided into three groups receiving either saline, standard P-gp inhibitor verapamil (25 mg/kg), or atorvastatin (10 mg/kg), 2 hrs prior to a single dose of daclatasvir (7 mg/kg). In addition, the markers of liver and kidney functions and muscle rhabdomyolysis were assessed. Further, histopathological examination of liver and kidney tissue and assessment of CYP3A4 level was done.

Results: The inhibitory effect of atorvastatin on Pgp activity and expression was manifested by increased serosal transport of the standard rhodamine 123, as well as daclatasvir. In vivo, Cmax (peak plasma concentration) and area under the curve (AUC (0‐t)) of daclatasvir after atorvastatin treatment increased compared to the vehicle group but not in a significant manner. On the other hand, atorvastatin caused a significant increase in the clearance of daclatasvir. Concomitant administration of atorvastatin with daclatasvir significantly decreased CYP3A4 content compared to the control group. The combination also showed increased liver enzymes and some pathological alterations in the liver.

Conclusion: Atorvastatin has a significant effect on P-gp mediated intestinal transport of daclatasvir; however, it did not affect the systemic bioavailability of a single oral dose of daclatasvir.

Keywords: Daclatasvir, atorvastatin, pharmacokinetics interaction, P-glycoprotein, CYP3A4, toxicity.

Graphical Abstract

[1]
Hajarizadeh, B.; Razavi-Shearer, D.; Merat, S.; Alavian, S.M.; Malekzadeh, R.; Razavi, H. Liver disease burden of hepatitis C virus infection in Iran and the potential impact of various treatment strategies on the disease burden. Hepat. Mon., 2016, 16(7), e37234.
[http://dx.doi.org/10.5812/hepatmon.37234] [PMID: 27642346]
[2]
Chhatwal, J.; Wang, X.; Ayer, T.; Kabiri, M.; Chung, R.T.; Hur, C.; Donohue, J.M.; Roberts, M.S.; Kanwal, F. Hepatitis C disease burden in the United States in the era of oral direct-acting antivirals. Hepatology, 2016, 64(5), 1442-1450.
[http://dx.doi.org/10.1002/hep.28571] [PMID: 27015107]
[3]
Gower, E.; Estes, C.; Blach, S.; Razavi-Shearer, K.; Razavi, H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J. Hepatol., 2014, 61(1)(Suppl.), S45-S57.
[http://dx.doi.org/10.1016/j.jhep.2014.07.027] [PMID: 25086286]
[4]
Bunchorntavakul, C.; Reddy, K.R. Review article: The efficacy and safety of daclatasvir in the treatment of chronic hepatitis C virus infection. Aliment. Pharmacol. Ther., 2015, 42(3), 258-272.
[http://dx.doi.org/10.1111/apt.13264] [PMID: 26014906]
[5]
Gandhi, Y.; Eley, T.; Fura, A.; Li, W.; Bertz, R.J.; Garimella, T. daclatasvir: a review of preclinical and clinical pharmacokinetics. Clin. Pharmacokinet., 2018, 57(8), 911-928.
[http://dx.doi.org/10.1007/s40262-017-0624-3] [PMID: 29353349]
[6]
Watkins, P.B.; Wrighton, S.A.; Schuetz, E.G.; Molowa, D.T.; Guzelian, P.S. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J. Clin. Invest., 1987, 80(4), 1029-1036.
[http://dx.doi.org/10.1172/JCI113156] [PMID: 3654968]
[7]
Amin, M.L. P-glycoprotein Inhibition for optimal drug delivery. Drug Target Insights, 2013, 7, 27-34.
[http://dx.doi.org/10.4137/DTI.S12519] [PMID: 24023511]
[8]
Srivalli, K.M.; Lakshmi, P.K. Overview of P-glycoprotein inhibitors: A rational outlook. Braz. J. Pharm. Sci., 2012, 48(3), 353-367.
[http://dx.doi.org/10.1590/S1984-82502012000300002]
[9]
Fardel, O.; Kolasa, E.; Le Vee, M. Environmental chemicals as substrates, inhibitors or inducers of drug transporters: Implication for toxicokinetics, toxicity and pharmacokinetics. Expert Opin. Drug Metab. Toxicol., 2012, 8(1), 29-46.
[http://dx.doi.org/10.1517/17425255.2012.637918] [PMID: 22176607]
[10]
Lin, J.H.; Yamazaki, M. Role of P-glycoprotein in pharmacokinetics: Clinical implications. Clin. Pharmacokinet., 2003, 42(1), 59-98.
[http://dx.doi.org/10.2165/00003088-200342010-00003] [PMID: 12489979]
[11]
Negro, F.; Sanyal, A.J. Hepatitis C virus, steatosis and lipid abnormalities: Clinical and pathogenic data. Liver Int., 2009, 29(Supp.l 2), 26-37.
[PMID: 19187070]
[12]
Louie, K.S.; St Laurent, S.; Forssen, U.M.; Mundy, L.M.; Pimenta, J.M. The high comorbidity burden of the hepatitis C virus infected population in the United States. BMC Infect. Dis., 2012, 12(1), 86.
[http://dx.doi.org/10.1186/1471-2334-12-86] [PMID: 22494445]
[13]
Butt, A.A.; Yan, P.; Bonilla, H.; Abou-Samra, A.B.; Shaikh, O.S.; Simon, T.G.; Chung, R.T.; Rogal, S.S. Effect of addition of statins to antiviral therapy in hepatitis C virus-infected persons: Results from ERCHIVES. Hepatology, 2015, 62(2), 365-374.
[http://dx.doi.org/10.1002/hep.27835] [PMID: 25847403]
[14]
Sun, H.Y.; Singh, N. Antimicrobial and immunomodulatory attributes of statins: Relevance in solid-organ transplant recipients. Clin. Infect. Dis., 2009, 48(6), 745-755.
[http://dx.doi.org/10.1086/597039] [PMID: 19193110]
[15]
Marrone, G.; Russo, L.; Rosado, E.; Hide, D.; García-Cardeña, G.; García-Pagán, J.C.; Bosch, J.; Gracia-Sancho, J. The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins. J. Hepatol., 2013, 58(1), 98-103.
[http://dx.doi.org/10.1016/j.jhep.2012.08.026] [PMID: 22989565]
[16]
Kumar, S.; Grace, N.D.; Qamar, A.A. Statin use in patients with cirrhosis: A retrospective cohort study. Dig. Dis. Sci., 2014, 59(8), 1958-1965.
[http://dx.doi.org/10.1007/s10620-014-3179-2] [PMID: 24838495]
[17]
Lewis, J.H.; Mortensen, M.E.; Zweig, S.; Fusco, M.J.; Medoff, J.R.; Belder, R. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology, 2007, 46(5), 1453-1463.
[http://dx.doi.org/10.1002/hep.21848] [PMID: 17668878]
[18]
Chang, C.H.; Chang, Y.C.; Lee, Y.C.; Liu, Y.C.; Chuang, L.M.; Lin, J.W. Severe hepatic injury associated with different statins in patients with chronic liver disease: A nationwide population-based cohort study. J. Gastroenterol. Hepatol., 2015, 30(1), 155-162.
[http://dx.doi.org/10.1111/jgh.12657] [PMID: 25041076]
[19]
Palleria, C.; Roberti, R.; Iannone, L.F.; Tallarico, M.; Barbieri, M.A.; Vero, A.; Manti, A.; De Sarro, G.; Spina, E.; Russo, E. Clinically relevant drug interactions between statins and antidepressants. J. Clin. Pharm. Ther., 2020, 45(2), 227-239.
[http://dx.doi.org/10.1111/jcpt.13058] [PMID: 31587356]
[20]
Holtzman, C.W.; Wiggins, B.S.; Spinler, S.A. Role of P-glycoprotein in statin drug interactions. Pharmacotherapy, 2006, 26(11), 1601-1607.
[http://dx.doi.org/10.1592/phco.26.11.1601] [PMID: 17064205]
[21]
Wiggins, B.S.; Saseen, J.J.; Page, R.L., II; Reed, B.N.; Sneed, K.; Kostis, J.B.; Lanfear, D.; Virani, S.; Morris, P.B. Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: A scientific statement from the American heart association. Circulation, 2016, 134(21), e468-e495.
[http://dx.doi.org/10.1161/CIR.0000000000000456] [PMID: 27754879]
[22]
Bansal, T.; Mishra, G.; Jaggi, M.; Khar, R.K.; Talegaonkar, S. Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats. Eur. J. Pharm. Sci., 2009, 36(4-5), 580-590.
[http://dx.doi.org/10.1016/j.ejps.2008.12.005] [PMID: 19135530]
[23]
Shah, K.A.; Patel, M.B.; Shah, S.S.; Chauhan, K.N.; Parmar, P.K.; Patel, N.M. Antihyperlipidemic activity of Mangifera indica l. leaf extract on rats fed with high cholesterol diet. Pharm. Sin., 2010, 1(2), 156-161.
[24]
Mishra, R.; Mir, S.R.; Amin, S. Polymeric nanoparticles for improved bioavailability of cilnidipine. Int. J. Pharm. Pharm. Sci., 2017, 9(4), 129-3.
[http://dx.doi.org/10.22159/ijpps.2017v9i4.15786]
[25]
Ghanem, C.I.; Gómez, P.C.; Arana, M.C.; Perassolo, M.; Delli Carpini, G.; Luquita, M.G.; Veggi, L.M.; Catania, V.A.; Bengochea, L.A.; Mottino, A.D. Induction of rat intestinal P-glycoprotein by spironolactone and its effect on absorption of orally administered digoxin. J. Pharmacol. Exp. Ther., 2006, 318(3), 1146-1152.
[http://dx.doi.org/10.1124/jpet.106.105668] [PMID: 16740618]
[26]
Dogra, A.; Bhatt, S.; Magotra, A.; Sharma, A.; Kotwal, P.; Gour, A.; Wazir, P.; Singh, G.; Nandi, U. Intervention of curcumin on oral pharmacokinetics of daclatasvir in rat: A possible risk for long-term use. Phytother. Res., 2018, 32(10), 1967-1974.
[http://dx.doi.org/10.1002/ptr.6123] [PMID: 29806225]
[27]
Nadig, S.; Jacob, J.T. Quantitative estimation of daclatasvir in drug substances and formulated drug product by UPLC. Pharm. Lett., 2016, 8(13), 280-284.
[28]
Banni, M.; Messaoudi, I.; Said, L.; El Heni, J.; Kerkeni, A.; Said, K. Metallothionein gene expression in liver of rats exposed to cadmium and supplemented with zinc and selenium. Arch. Environ. Contam. Toxicol., 2010, 59(3), 513-519.
[http://dx.doi.org/10.1007/s00244-010-9494-5] [PMID: 20238111]
[29]
Kong, L.L.; Zhuang, X.M.; Yang, H.Y.; Yuan, M.; Xu, L.; Li, H. Inhibition of P-glycoprotein gene expression and function enhances triptolide-induced hepatotoxicity in mice. Sci. Rep., 2015, 5(1), 11747.
[http://dx.doi.org/10.1038/srep11747] [PMID: 26134275]
[30]
Yuan, J.S.; Reed, A.; Chen, F.; Stewart, C.N., Jr Statistical analysis of real-time PCR data. BMC Bioinformatics, 2006, 7(1), 85.
[http://dx.doi.org/10.1186/1471-2105-7-85] [PMID: 16504059]
[31]
Chung, J.W.; Yang, S.H.; Choi, J.S. Effects of lovastatin on the pharmacokinetics of nicardipine in rats. Biopharm. Drug Dispos., 2010, 31(7), 436-441.
[http://dx.doi.org/10.1002/bdd.721] [PMID: 20824619]
[32]
Badwan, A.; Remawi, M.; Qinna, N.; Elsayed, A.; Arafat, T.; Melhim, M.; Hijleh, O.A.; Idkaidek, N.M. Enhancement of oral bioavailability of insulin in humans. Neuroendocrinol. Lett., 2009, 30(1), 74-78.
[PMID: 19300394]
[33]
Bancroft, J.D.; Stevens, A. Theory and Practice of Histological Techniques, 4th ed; Churchill Livingstone: New York, 1996.
[34]
Wang, E.; Casciano, C.N.; Clement, R.P.; Johnson, W.W. HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharm. Res., 2001, 18(6), 800-806.
[http://dx.doi.org/10.1023/A:1011036428972] [PMID: 11474784]
[35]
Zhang, Y.; Guo, X.; Lin, E.T.; Benet, L.Z. Overlapping substrate specificities of cytochrome P450 3A and P-glycoprotein for a novel cysteine protease inhibitor. Drug Metab. Dispos., 1998, 26(4), 360-366.
[PMID: 9531525]
[36]
Hong, S.P.; Chang, K.S.; Choi, D.H.; Choi, J.S. Effect of atorvastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats. Arch. Pharm. Res., 2007, 30(1), 90-95.
[http://dx.doi.org/10.1007/BF02977783] [PMID: 17328247]
[37]
Garimella, T.; You, X.; Wang, R.; Huang, S.P.; Kandoussi, H.; Bifano, M.; Bertz, R.; Eley, T. A Review of daclatasvir drug-drug interactions. Adv. Ther., 2016, 33(11), 1867-1884.
[http://dx.doi.org/10.1007/s12325-016-0407-5] [PMID: 27664109]
[38]
Garimella, T.; Wang, R.; Luo, W.L.; Hwang, C.; Sherman, D.; Kandoussi, H.; Marbury, T.C.; Alcorn, H.; Bertz, R.; Bifano, M. Single-dose pharmacokinetics and safety of daclatasvir in subjects with renal function impairment. Antivir. Ther., 2015, 20(5), 535-543.
[http://dx.doi.org/10.3851/IMP2941] [PMID: 25654812]
[39]
Montgomery, M.; Ho, N.; Chung, E.; Marzella, N. Daclatasvir (Daklinza): A Treatment option for chronic hepatitis C infection. P&T, 2016, 41(12), 751-755.
[PMID: 27990076]
[40]
Yeo, K.R.; Yeo, W.W. Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes. Br. J. Clin. Pharmacol., 2001, 51(5), 461-470.
[http://dx.doi.org/10.1046/j.1365-2125.2001.01386.x]
[41]
Anzai, N.; Kanai, Y.; Endou, H. Organic anion transporter family: Current knowledge. J. Pharmacol. Sci., 2006, 100(5), 411-426.
[42]
Chandrasekaran, B.; Abed, S.N.; Al-Attraqchi, O.; Kuche, K.; Tejade, R.K. Chapter 21 Computer-Aided Prediction of Pharmacokinetic (ADMET) Properties. In: Advances in Pharmaceutical Product Development and Research; Tejade, R.K., Ed.;, 2018; II, pp. 731-755.
[43]
Schachter, M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: An update. Fundam. Clin. Pharmacol., 2005, 19(1), 117-125.
[http://dx.doi.org/10.1111/j.1472-8206.2004.00299.x] [PMID: 15660968]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy