The growing interest in the composition and effects of microbiota raised the question how drug pharmacokinetics could be influenced by concomitant application of probiotics. The aim of this study was to find whether probiotic E. coli strain Nissle 1917 (EcN) influences the pharmacokinetics of concomitantly taken antiarrhythmic drug amiodarone (AMI). Live bacterial suspension of probiotic EcN (or non-probiotic E. coli strain ATCC 25922) was applied orally to male Wistar rats for seven days, while a control group of rats was treated with a saline solution. On the eighth day, the amiodarone hydrochloride was administered as one single oral dose (50 mg/kg) to all rats (N = 60). After 0, 1, 2, 3, 4, 5.5, 7, 9, 14, 22, and 30 hours, blood samples were taken from the rat abdominal aorta. The plasma level of AMI and its metabolite N-desethylamiodarone (DEA) was determined using the HPLC with UV detection. Administration of EcN led to a 43% increase of AMI AUC0-30 in comparison with control samples. However, this effect was not observed if EcN was replaced by a reference non-probiotic E. coli strain. Thus, EcN administration was most probably responsible for better drug absorption from the gastrointestinal tract. Plasma levels of DEA were also increased in plasma samples from animals treated with EcN. This change was again not found in the experiment with the reference non-probiotic strain. Higher DEA levels in samples from EcN-treated rats may be explained either by better absorption of AMI and/or by an increased activity of CYP2C forms, known to participate in metabolism of this drug, after EcN administration. In this paper, it is documented that concomitantly taken probiotic EcN may modulate pharmacokinetics of a drug; in this case, it led to an increased bioavailability of AMI.

Department of Medical Chemistry and Biochemistry Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

Department of Microbiology Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

Department of Pharmacology and Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

Institute of Microbiology Academy of Sciences of the Czech Republic Prague Czech Republic

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Sommer F, Bäckhed F (2013) The gut microbiota-masters of host development and physiology. Nat Rev Microbiol 11 4: 227–238. PubMed

Tlaskalová-Hogenová H, Stěpánková R, Kozáková H, Hudcovic T, Vannucci L, et al. (2011) The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cell Mol Immunol 8 2: 110–120. PubMed PMC

Meijerink M, Mercenier A, Wells JM (2013) Challenges in translational research on probiotic lactobacilli: from in vitro assays to clinical trials. Benef Microbes 4 1: 83–100. PubMed

Stojančevic M, Bojič G, Salami HA, Mikov M (2013) The influence of intestinal tract and probiotics on the fate of orally administered drugs. Curr Issues Mol Biol 16 2: 55–68. PubMed

Haiser HJ, Gootenberg DB, Chatman K, Sirasani G, Balskus EP, et al. (2013) Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science 341 6143: 295–8. PubMed PMC

Grozdanov L, Zähringer U, Blum-Oehler G, Brade L, Henne A, et al. (2002) A single nucleotide exchange in the wzy gene is responsible for the semirough O6 lipopolysaccharide phenotype and serum sensitivity of Escherichia coli strain Nissle 1917. J Bacteriol 184 21: 5912–5925. PubMed PMC

Sonnenborn U, Schulze J (2009) The non-pathogenic Escherichia coli Nissle 1917 – features of a versatile probiotic. Microbial Ecology Hlth Dis 21: 122–158.

Westendorf AM, Gunzer F, Deppenmeier S, Tapadar D, Hunger JK, et al. (2005) Intestinal immunity of Escherichia coli Nissle 1917: a safe carrier for therapeutic molecules. FEMS Immunol Med Microbiol 43: 373–384. PubMed

Tannock GW, Tiong IS, Priest P, Munro K, Taylor C, et al. (2011) Testing probiotic strain Escherichia coli Nissle 1917 (Mutaflor) for its ability to reduce carriage of multidrug-resistant E. coli by elderly residents in long283 term care facilities. J Med Microbiol 60: 366–370. PubMed

Krammer H, Kämper H, von Bünau R, Zieseniß E, Stange C, et al. (2006) Probiotische Arzneimitteltherapie mit E. coli Stamm Nissle 1917 (EcN): Ergebnisse einer prospektiven Datenerhebung mit 3807 Patienten. Z Gastroenterol 44: 651–656. PubMed

Henker J, Laass M, Blokhin BM, Bolbot YK, Maydannik VG, et al. (2007) The probiotic Escherichia coli strain Nissle 1917 (EcN) stops acute diarrhoea in infants and toddlers. Eur J Pediatrics 166: 311–318. PubMed PMC

Guarner F, Schlaafsma GJ (1998) Probiotics. Int J Food Microbiol 39: 237–238. PubMed

Roden DM (1993) Current status of class III antiarrhythmic drug therapy. Am J Cardiol 72: 44B–49B. PubMed

Van Herendael H, Dorian P (2010) Amiodarone for the treatment and prevention of ventricular fibrillation and ventricular tachycardia. Vasc Hlth Risk Management 6: 465–472. PubMed PMC

Ohyama K, Nakajima M, Nakamura S, Shimada N, Yamazaki H, et al. (2000) A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation: An approach to predict the contribution with relative activity factor. Drug Metab Dispos 28: 1303–1310. PubMed

Elsherbiny ME, El-Kadi AOS, Brocks DR (2008) The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole. J Pharm Pharmaceut Sci 11 1: 147–159. PubMed

Meng X, Mojaverian P, Doedée M, Lin E, Weinryb I, et al. (2001) Bioavailability of amiodarone tablets administered with and without food in healthy subjects. Am J Cardiol 87: 432–435. PubMed

Goldschlager N, Epstein AE, Naccarelli G, Olshansky B, Singh B (2000) Practical guidelines for clinicians who treat patients with amiodarone. Arch Intern Med 160: 1741–1748. PubMed

Al-Salami H, Butt G, Fawcett JP, Tucker IG, Golocorbin-Kon S, et al. (2008) Probiotic treatment reduces blood glucose levels and increases systemic absorption of gliclazide in diabetic rats. Eur J Drug Metabol Pharmacokinetics 33 2: 101–106. PubMed

Al-Salami H, Butt G, Tucker I, Skrbic R, Golocorbin-Kon S, et al. (2008) Probiotic pre-treatment reduces gliclazide permeation (ex vivo) in healthy rats but increases it in diabetic rats to the level seen in untreated healthy rats. Arch Drug Info 1: 35–41. PubMed PMC

Lee HJ, Zhang H, Orlovich DA, Fawcett JP (2012) The influence of probiotic treatment on sulfasalazine metabolism in rat. Xenobiotica 42 8: 791–797. PubMed

Kunes M, Kvetina J, Kholova D, Bures J, Tlaskalova-Hogenova H, et al. (2011) Absorption kinetics of 5-aminosalicylic acid in rat: influence of indomethacin-induced gastrointestinal lesions and Escherichia coli Nissle 1917 medication. Neuro Endocrinol Lett Suppl 1: 46–52. PubMed

Jun AS, Brocks DR (2001) High-performance liquid chromatographic assay of amiodarone in rat plasma. J Pharm Pharmaceut Sci 4 3: 263–268. PubMed

Sartor RB (2004) Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: Antibiotics, probiotics, and prebiotics. Gastroenterology 126: 1620–1633. PubMed

Chatelain P, Ferreira J, Laruel R, Ruysschaert JM (1986) Amiodarone-induced modifications of the phospholipid physical state. A fluorescence polarization study. Biochem Pharmacol 35 18: 3007–3013. PubMed

Boury F, Gautier J-C, Bouligand Y, Proust J-E (2001) Interfacial properties of amiodarone: the stabilizing effect of phosphate anions. Coll Surf B: Biointerfaces 20: 219–227. PubMed

Sigurdson HH, Kirch J, Lehr C-M (2013) Mucus as a barrier to lipohilic drugs. Intl J Pharmaceutics 453: 56–64. PubMed

Koenen A, Kroemer HK, Grube M, Meyer zu Schwabedissen HE (2011) Current understanding of hepatic and intestinal OATP-mediated drug-drug interactions. Expert Rev Clin Pharmacol 4 6: 729–742. PubMed

Le Vee M, Lecureur V, Stieger B, Fardel O (2009) Regulation of drug transporter expression in human hepatocytes exposed to the proinflammatory cytokines tumor necrosis factor-α or interleukin-6. Drug Metab Dispos 37 3: 685–693. PubMed

Jacobi CA, Malfertheiner P (2011) Escherichia coli Nissle 1917 (Mutaflor): New insights into an old probiotic bacterium. Dig Dis 29: 600–607. PubMed

Matuskova Z, Tunkova A, Anzenbacherova E, Zidek Z, Tlaskalova-Hogenova H, et al. (2009) Influence of probiotics on rat liver biotransformation enzymes. Neuroendocrinol Lett Suppl 1: 41–45. PubMed

Darwich AS, Neuhoff S, Jamei M, Rostami-Hodjegan A (2010) Interplay of metabolism and transport in determing oral drug absorption and gut wall metabolism: a simulation assessment using the “Advanced Dissolution, Absorption, Metabolism (ADAM)” model. Curr Drug Metab 11 9: 716–29. PubMed

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