Abstract
Aim:
Caderofloxacin is a new fluoroquinolone that is under phase III clinical trials in China. Here we examined the effects of caderofloxacin on rat hepatic cytochrome P450 (CYP450) isoforms as well as the potential of caderofloxacin interacting with co-administered drugs.
Methods:
Male rats were treated with caderofloxacin (9 mg/kg, ig) once or twice daily for 14 consecutive days. The effects of caderofloxacin on CYP3A, 2D6, 2C19, 1A2, 2E1 and 2C9 were evaluated using a “cocktail” of 6 probes (midazolam, dextromethorphan, omeprazole, theophylline, chlorzoxazone and diclofenac) injected on d 0 (prior to caderofloxacin exposure) and d 15 (after caderofloxacin exposure). Hepatic microsomes from the caderofloxacin-treated rats were used to assess CYP2E1 activity and chlorzoxazone metabolism. The expression of CYP2E1 mRNA and protein in hepatic microsomes was analyzed with RT-PCR and Western blotting, respectively.
Results:
Fourteen-day administration of caderofloxacin significantly increased the activity of hepatic CYP2E1, leading to enhanced metabolism of chlorzoxazone. In vitro microsomal study confirmed that CYP2E1 was a major metabolic enzyme involved in chlorzoxazone metabolism, and the 14-d administration of caderofloxacin significantly increased the activity of CYP2E1 in hepatic microsomes, resulting in increased formation of 6-hydroxychlorzoxazone. Furthermore, the 14-d administration of caderofloxacin significantly increased the expression of CYP2E1 mRNA and protein in liver microsomes, which was consistent with the pharmacokinetic results.
Conclusion:
Fourteen-day administration of caderofloxacin can induce the expression and activity of hepatic CYP2E1 in rats. When caderofloxacin is administered, a potential drug-drug interaction mediated by CYP2E1 induction should be considered.
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References
Biedenbach DJ, Sutton LD, Jones RN . Antimicrobial activity of CS-940, a new trifluorinated quinolone. Antimicrob Agents Chemother 1995; 39: 2325–30.
Masuda N, Takahashi Y, Otsuki M, Ibuki E, Miyoshi H, Nishino T . In vitro and in vivo antibacterial activities of CS-940, a new 6-fluoro-8-difluoromethoxy quinolone. Antimicrob Agents Chemother 1996; 40: 1201–7.
Miyazaki S, Domon H, Tateda K, Ohno A, Ishii Y, Matsumoto T, et al. In vitro and in vivo antibacterial activities of CS-940, a new fluoroquinolone, against isolates from patients with respiratory infections. Antimicrob Agents Chemother 1997; 41: 2582–5.
Spaggiari D, Geiser L, Daali Y, Rudaz S . Phenotyping of CYP450 in human liver microsomes using the cocktail approach. Anal Bioanal Chem 2014; 406: 4875–87.
Reginald FF . Probing the world of cytochrome P450 enzymes. Mol Interv 2004; 4: 157–62.
Youdim KA, Saunders KC . A review of LC-MS techniques and high-throughput approaches used to investigate drug metabolism bycytochrome P450s. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878: 1326–36.
Tanaka S, Uchida S, Inui N, Takeuchi K, Watanabe H, Namiki N . Simultaneous LC-MS/MS analysis of the plasma concentrations of a cocktail of 5 cytochrome P450 substrate drugs and their metabolites. Biol Pharm Bull 2014; 37: 18–25.
Ghassabian S, Chetty M, Tattam BN, Chem MC, Glen J, Rahme J, et al. A high-throughput assay using liquid chromatography-tandem mass spectrometry for simultaneous in vivo phenotyping of 5 major cytochrome p450 enzymes in patients. Ther Drug Monit 2009; 31: 239–46.
Ryu JY, Song IS, Sunwoo YE, Shon JH, Liu KH, Cha IJ, et al. Development of the "Inje cocktail" for high-throughput evaluation of five human cytochrome P450 isoforms in vivo. Clin Pharmacol Ther 2007; 82: 531–40.
Turpault S, Brian W, Van Horn R, Santoni A, Poitiers F, Donazzolo Y, et al. Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol 2009; 68: 928–35.
Jenkins J, Williams D, Deng Y, Collins DA, Kitchen VS . Eltrombopag, an oral thrombopoietin receptor agonist, has no impact on the pharmacokinetic profile of probe drugs for cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C9 and CYP2C19 in healthy men: a cocktail analysis. Eur J Clin Pharmacol 2010; 66: 67–76.
Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, et al. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr 2006; 42: 52–60.
Testa B, Pedretti A, Vistoli G . Reactions and enzymes in the metabolism of drugs and other xenobiotics. Drug Discov Today 2012; 17: 549–60.
Huang SM, Temple R, Throckmorton DC, Lesko LJ . Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin Pharmacol Ther 2007; 81: 298–304.
Liu H, Liu L, Li J, Mei D, Duan R, Hu N, et al. Combined contributions of impaired hepatic CYP2C11 and intestinal breast cancer resistance protein activities and expression to increased oral glibenclamide exposure in rats with streptozotocin-induced diabetes mellitus. Drug Metab Dispos 2012; 40: 1104–12.
Li X, Wang X, Li Y, Zhu J, Su X, Yao X, et al. The activity, protein, and mrna expression of CYP2E1 and CYP3A1 in rats after exposure to acute and chronichigh altitude hypoxia. High Alt Med Biol 2014; 15: 491–6.
Valencia-Olvera AC, Morán J, Camacho-Carranza R, Prospéro-García O, Espinosa-Aguirre JJ . CYP2E1 induction leads to oxidative stress and cytotoxicity in glutathione-depleted cerebellar granule neurons. Toxicol In Vitr>o 2014; 28: 1206–14.
Xu X, Liu HY, Liu L, Xie L, Liu XD . The influence of a newly developed quinolone: antofloxacin, on CYP activity in rats. Eur J Drug Metab Pharmacokinet 2008; 33: 1–7.
Fuhr U, Jetter A, Kirchheiner J . Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the "cocktail" approach. Clin Pharmacol Ther 2007; 81: 270–83.
Spaggiari D, Geiser L, Daali Y, Rudaz S . A cocktail approach for assessing the in vitro activity of human cytochrome P450s: An overview of current methodologies. J Pharm Biomed Anal 2014; S0731–7085: 00145–9.
Nordmark A, Andersson A, Baranczewski P, Wanag E, Ståhle L . Assessment of interaction potential of AZD2066 using in vitro metabolism tools, physiologically based pharmacokinetic modelling and in vivo cocktail data. Eur J Clin Pharmacol 2014; 70: 167–78.
Snyder BD, Rowland A, Polasek TM, Miners JO, Doogue MP . Evaluation of felodipine as a potential perpetrator of pharmacokinetic drug-drug interactions. Eur J Clin Pharmacol 2014; 70: 1115–22.
Bosilkovska M, Déglon J, Samer C, Walder B, Desmeules J, Staub C, et al. Simultaneous LC-MS/MS quantification of P-glycoprotein and cytochrome P450 probe substrates and their metabolites in DBS and plasma. Bioanalysis 2014; 6: 151–64.
Tomalik-Scharte D, Jetter A, Kinzig-Schippers M, Skott A, Sörgel F, Klaassen T, et al. Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers. Drug Metab Dispos. 2005; 33: 1859–66.
Zuber R, Anzenbacherová E, Anzenbacher P . Cytochromes P450 and experimental models of drug metabolism. J Cell Mol Med 2002; 6: 189–98.
Martignoni M, Groothuis GM, de Kanter R . Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2006; 2: 875–94.
Joshi M, Tyndale RF . Regional and cellular distribution of CYP2E1 in monkey brain and its inductionby chronic nicotine. Neuropharmacology 2006; 50: 568–75.
Yan J, He X, Feng S, Zhai Y, Ma Y, Liang S, et al. Up-regulation on cytochromes P450 in rat mediated by total alkaloid extract from Corydalis yanhusuo. BMC Complement Altern Med 2014; 14: 306.
Dey A . Cytochrome P450 2E1: its clinical aspects and a brief perspective on the current research scenario. Subcell Biochem 2013; 67: 1–104.
Neuwirth C, Mosesso P, Pepe G, Fiore M, Malfatti M, Turteltaub K, et al. Furan carcinogenicity: DNA binding and genotoxicity of furan in rats in vivo. Mol Nutr Food Res 2012; 56: 1363–74.
Qi XM, Miao LL, Cai Y, Gong LK, Ren J . ROS generated by CYP450, especially CYP2E1, mediate mitochondrial dysfunction induced by tetrandrine in rat hepatocytes. Acta Pharmacol Sin 2013; 34: 1229–36.
Das J, Ghosh J, Manna P, Sil PC . Acetaminophen induced acute liver failure via oxidative stress and JNK activation: protective role of taurine by the suppression of cytochrome P450 2E1. Free Radic Res 2010; 44: 340–55.
Peterson TC, Peterson MR, Wornell PA, Blanchard MG, Gonzalez FJ . Role of CYP1A2 and CYP2E1 in the pentoxifylline ciprofloxacin drug interaction. Biochem Pharmacol 2004; 68: 395–402.
Alshammari TM, Larrat EP, Morrill HJ, Caffrey AR, Quilliam BJ, LaPlante KL . Risk of hepatotoxicity associated with fluoroquinolones: a national case-control safety study. Am J Health Syst Pharm 2014; 71: 37–43.
Orman ES, Conjeevaram HS, Vuppalanchi R, Freston JW, Rochon J, Kleiner DE, et al. Clinical and histopathologic features of fluoroquinolone-induced liver injury. Clin Gastroenterol Hepatol 2011; 9: 517–523.e3.
Arinç E, Arslan S, Bozcaarmutlu A, Adali O . Effects of diabetes on rabbit kidney and lung CYP2E1 and CYP2B4 expression and drug metabolism and potentiation of carcinogenic activity of N-nitrosodimethylamine in kidney and lung. Food Chem Toxicol 2007; 45: 107–18.
Hines LE, Murphy JE . Potentially harmful drug-drug interactions in the elderly: a review. Am J Geriatr Pharmacother 2011; 9: 364–77.
Zhou SF, Wang B, Yang LP, Liu JP . Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev 2010; 42: 268–354.
Liu L, Pan X, Liu HY, Liu XD, Yang HW, Xie L, et al. Modulation of pharmacokinetics of theophylline by antofloxacin, a novel 8-amino-fluoroquinolone, in humans. Acta Pharmacol Sin 2011; 32: 1285–93.
O'Donnell JA, Gelone SP . Fluoroquinolones. Infect Dis Clin North Am 2000; 14: 489–513.
Zhang L, Wei MJ, Zhao CY, Qi HM . Determination of the inhibitory potential of 6 fluoroquinolones on CYP1A2 and CYP2C9 in human liver microsomes. Acta Pharmacol Sin 2008; 29: 1507–14.
Acknowledgements
The project was supported by the National Natural Science Foundation of China (No 81473273, 81373482 and 81573490), the Fundamental Research Funds for the Central Universities (2015PT042, ZD2014YX0026, and PT2014YX0057) and the Priority Academic Program for Development of the Jiangsu Higher Education Institutions.
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Liu, L., Miao, Mx., Zhong, Zy. et al. Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats. Acta Pharmacol Sin 37, 561–570 (2016). https://doi.org/10.1038/aps.2015.160
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DOI: https://doi.org/10.1038/aps.2015.160
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