Abstract
Macrolide antibiotics penetrate in the lung against steep concentration gradients into the epithelial lining fluid (ELF) and broncho-alveolar cells (BAC). Since they interact with ABCB1, ABCC2, and organic anion transporting proteins (OATPs), which are localized to lung tissue, pulmonary concentration may be influenced by rifampicin (RIF), an inducer and modulator of efflux and uptake transporters. We measured concentrations of tulathromycin (TM) in plasma, ELF and BAC in 21 warm-blooded foals 24 and 192 h after first and last intramuscular injection of 2.5 mg/kg TM once weekly for 6 weeks. In 11 foals, TM was combined with RIF (10 mg/kg twice daily), and mRNA expression of ABCB1 and ABCC2 in BAC was assessed before and after RIF. Affinity of TM to ABCB1 and ABCC2 was measured by transport assays using cell monolayers and membrane vesicles of MDCKII and 2008 cells transfected with ABCB1 and ABCC2, respectively. At steady state, TM concentrated manifold in ELF and BAC. Comedication of RIF significantly decreased the AUC of TM (18.5 ± 4.0 versus 24.4 ± 3.7 µg × h/ml, p < 0.05) and lowered its concentrations in plasma (24 h, 0.17 ± 0.05 versus 0.24 ± 0.05 µg/ml; 192 h, 0.05 ± 0.01 versus 0.06 ± 0.01 µg/ml) and BAC (24 h, 0.84 ± 0.36 versus 1.56 ± 1.02 µg/ml; 192 h, 0.60 ± 0.23 versus 1.23 ± 0.90 µg/ml, all p < 0.05). Treatment with rifampicin did not markedly induce ABCB1 and ABCC2 expression. TM had no affinity to ABCB1 and ABCC2 in vitro. Concentration of TM in the lung of foals was significantly lowered by comedication of rifampicin most likely caused by extrapulmonary mechanisms leading to lower plasma concentrations.
Similar content being viewed by others
Abbreviations
- ABCB1:
-
P-glycoprotein
- ABCC2:
-
multidrug resistance proteins 2 (MRP2)
- ABCG2:
-
breast cancer resistance protein (BCRP)
- ABCC7:
-
cystic fibrosis transmembrane conductance regulator (CFTR)
- BAC:
-
broncho-alveolar cells
- ELF:
-
epithelial lining fluid
- LC-MS/MS:
-
liquid chromatography-tandem mass spectrometry
- MDCK cells:
-
Madin–Darby canine kidney cells
- OATP:
-
organic anion transporting protein
References
Albermann N, Schmitz-Winnenthal FH, Z’graggen K et al (2005) Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem Pharmacol 70:949–958
Baldwin DR, Wise R, Andrews JM, Ashby JP, Honeybourne D (1990) Azithromycin concentrations at the sites of pulmonary infection. Eur Respir J 3:886–890
Benchaoui HA, Nowakowski M, Sherington J, Rowan TG, Sunderland SJ (2004) Pharmacokinetics and lung tissue concentrations of tulathromycin in swine. J Vet Pharmacol Ther 27:203–210
Beringer P, Huynh KM, Kriengkauykiat J et al (2005) Absolute bioavailability and intracellular pharmacokinetics of azithromycin in patients with cystic fibrosis. Antimicrob Agents Chemother 49:5013–5017
Bosnar M, Kelneric Z, Munic V, Erakovic V, Parnham MJ (2005) Cellular uptake and efflux of azithromycin, erythromycin, clarithromycin, telithromycin, and cethromycin. Antimicrob Agents Chemother 49:2372–2377
Conte JE Jr, Golden JA, Duncan S, McKenna E, Zurlinden E (1995) Intrapulmonary pharmacokinetics of clarithromycin and of erythromycin. Antimicrob Agents Chemother 39:334–338
Damiani D, Michieli M, Michelutti A et al (1993) Expression of multidrug resistance gene (MDR-1) in human normal leukocytes. Haematologica 78:12–17
European Medicines Agency (EMEA), Committee For Veterinary Medicinal Products (2004) Tulathromycin Summary Report (2)
Evans NA (2005) Tulathromycin: an overview of a new triamilide antibiotic for livestock respiratory disease. Vet Ther 6:83–95
Fardel O, Lecureur V, Loyer P, Guillouzo A (1995) Rifampicin enhances anti-cancer drug accumulation and activity in multidrug-resistant cells. Biochem Pharmacol 49:1255–1260
Farr B, Mandell GL (1982) Rifampin. Med Clin North Am 66:157–168
Galer D, Hessong S, Beato B et al (2004) An analytical method for the analysis of tulathromycin, an equilibrating triamilide, in bovine and porcine plasma and lung. J Agric Food Chem 52:2179–2191
Hillidge CJ (1987) Use of erythromycin–rifampin combination in treatment of Rhodococcus equi pneumonia. Vet Microbiol 14:337–342
Jacks St, Gíguère St, Grouwall RR et al (2001) Pharmacokinetics of azithromycin and concentration in body fluids and bronchoalveolar cells in foals. Am J Vet Res 62:1870–1875
Klimecki WT, Futscher BW, Grogan TM, Dalton WS (1994) P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood 83:2451–2458
Kullak-Ublick GA, Ismair MG, Stieger B et al (2001) Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 120:525–533
Labro MT, Abdelghaffar H, Babin-Chevaye C (2004) Interaction of the new ketolide ABT-773 (cethromycin) with human polymorphonuclear neutrophils and the phagocytic cell line PLB-985 in vitro. Antimicrob Agents Chemother 48:1096–1104
Labro MT, Babin-Chevaye C, Mergey M (2005) Accumulation of azithromycin and roxithromycin in tracheal epithelial fetal cell lines expressing wild type or mutated cystic fibrosis transmembrane conductance regulator protein (CFTR). J Chemother 17:385–392
Lau YY, Okochi H, Huang Y, Benet LZ (2006) Multiple transporters affect the disposition of atorvastatin and its two active hydroxy metabolites: application of in vitro and ex situ systems. J Pharmacol Exp Ther 316:762–771
Laupeze B, Amiot L, Payen L et al (2001) Multidrug resistance protein (MRP) activity in normal mature leukocytes and CD34-positive hematopoietic cells from peripheral blood. Life Sci 68:1323–1331
Meijer WG, Prescott JF (2004) Rhodococcus equi. Vet Res 35:383–396
Nichterlein T, Kretschmar M, Schadt A et al (1998) Reduced intracellular activity of antibiotics against Listeria monocytogenes in multidrug resistant cells. Int J Antimicrob Agents 10:119–125
Nowakowski MA, Inskeep PB, Risk JE et al (2004) Pharmacokinetics and lung tissue concentrations of tulathromycin, a new triamilide antibiotic, in cattle. Vet Ther 5:60–74
Olsen KM, San Pedro G, Gann LP, Gubbins PO, Halinski DM, Campbell GD Jr (1996) Intrapulmonary pharmacokinetics of azithromycin in healthy volunteers given five oral doses. Antimicrob Agents Chemother 40:2582–2585
Oswald S, Haenisch S, Fricke C et al (2006) Intestinal expression of P-glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate-glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans. Clin Pharmacol Ther 79:206–217
Rodvold KA, Danziger LH, Gotfried MH (2003) Steady-state plasma and bronchopulmonary concentrations of intravenous levofloxacin and azithromycin in healthy adults. Antimicrob Agents Chemother 47:2450–2457
Scheuch E, Spieker J, Venner M, Siegmund W (2007) Quantitative determination of the macrolide antibiotic tulathromycin in plasma and broncho-alveolar cells of foals using tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 850:464–470
Seithel A, Eberl S, Singer K et al (2007) The influence of macrolide antibiotics on the uptake of organic anions and drugs mediated by OATP1B1 and OATP1B3. Drug Metab Dispos 35:779–786
Seral C, Carryn S, Tulkens PM, Van Bambeke F (2003a) Influence of P-glycoprotein and MRP efflux pump inhibitors on the intracellular activity of azithromycin and ciprofloxacin in macrophages infected by Listeria monocytogenes or Staphylococcus aureus. J Antimicrob Chemother 51:1167–1173
Seral C, Michot JM, Chanteux H, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F (2003b) Influence of P-glycoprotein inhibitors on accumulation of macrolides in J774 murine macrophages. Antimicrob Agents Chemother 47:1047–1051
Sugie M, Asakura E, Zhao YL et al (2004) Possible involvement of the drug transporters P glycoprotein and multidrug resistance-associated protein Mrp2 in disposition of azithromycin. Antimicrob Agents Chemother 48:809–814
Tirona RG, Leake BF, Wolkoff AW, Kim RB (2003) Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J Pharmacol Exp Ther 304:223–228
van der Deen M, de Vries EG, Timens W, Scheper RJ, Timmer-Bosscha H, Postma DS (2005) ATP-binding cassette (ABC) transporters in normal and pathological lung. Respir Res 6:59
Vavricka SR, Van Montfoort J, Ha HR, Meier PJ, Fattinger K (2002) Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology 36:164–172
Xu C, Li CY, Kong AN (2005) Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharm Res 28:249–268
Ziglam HM, Baldwin DR, Daniels I, Andrew JM, Finch RG (2002) Rifampicin concentrations in bronchial mucosa, epithelial lining fluid, alveolar macrophages and serum following a single 600 mg oral dose in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother 50:1011–1015
Acknowledgments
The authors thank Gitta Schumacher, Sabine Bade, and Danilo Wegner for their excellent technical assistance.
Conflict of interest
The authors declare that they have no conflict of interest.
Financial support
The clinical part of the study was generously supported by the Paul-Schockmoehle Lewitz Stud, Neustadt-Glewe, Germany and a research grant of Pfizer, Germany. The analytic part was supported the grant 01ZZ0403 (BMBF-NBL3) and the molecular and cell biological part by the grant 03IP612 (InnoProfile) of the German Federal Ministry for Education and Research.
Ethical approval
The corresponding State Authority of Mecklenburg/Vorpommern (Landesveterinär–und Lebensmitteluntersuchungsamt) has been notified and relevant reference numbers are LALLF M-V/TSD/7221.3-2.1-010/06 and LVL M-V/TSD/7221.3-2.1-021/04.
Results of this paper were presented as a poster at the Annual Meeting of the German Society for Equine Medicine (DVG-Pferdekrankheiten), February 2006.
Author information
Authors and Affiliations
Corresponding author
Additional information
Monica Venner and Jette Peters contributed in equal parts to this work.
Rights and permissions
About this article
Cite this article
Venner, M., Peters, J., Höhensteiger, N. et al. Concentration of the macrolide antibiotic tulathromycin in broncho-alveolar cells is influenced by comedication of rifampicin in foals. Naunyn-Schmied Arch Pharmacol 381, 161–169 (2010). https://doi.org/10.1007/s00210-009-0481-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-009-0481-1