title: Concentration of the macrolide antibiotic tulathromycin in broncho-alveolar cells is influenced by comedication of rifampicin in foals.
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 microg x h/ml, p < 0.05) and lowered its concentrations in plasma (24 h, 0.17 +/- 0.05 versus 0.24 +/- 0.05 microg/ml; 192 h, 0.05 +/- 0.01 versus 0.06 +/- 0.01 microg/ml) and BAC (24 h, 0.84 +/- 0.36 versus 1.56 +/- 1.02 microg/ml; 192 h, 0.60 +/- 0.23 versus 1.23 +/- 0.90 microg/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.
authors.affiliation: Clinic for Horses, University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173 Hannover, Germany.
authors.forename: Monica
authors.initials: M
authors.lastname: Venner
authors.forename: Jette
authors.initials: J
authors.lastname: Peters
authors.forename: Nina
authors.initials: N
authors.lastname: Höhensteiger
authors.forename: Birthe
authors.initials: B
authors.lastname: Schock
authors.forename: Alexa
authors.initials: A
authors.lastname: Bornhorst
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.forename: Ulrike
authors.initials: U
authors.lastname: Adam
authors.forename: Eberhard
authors.initials: E
authors.lastname: Scheuch
authors.forename: Werner
authors.initials: W
authors.lastname: Weitschies
authors.forename: Dieter
authors.initials: D
authors.lastname: Rosskopf
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: Werner
authors.initials: W
authors.lastname: Siegmund
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D019540:Area Under Curve; D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D004187:Disaccharides / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D006571:Heterocyclic Compounds / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics; D006736:Horses; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D012293:Rifampin / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D018942:Macrolides
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D000904:Antibiotics, Antitubercular; D004187:Disaccharides; D006571:Heterocyclic Compounds; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D012293:Rifampin; C485204:tulathromycin; D018942:Macrolides