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.

Oral Absorption of Clarithromycin Is Nearly Abolished by Chronic Comedication of Rifampicin in Foals

“…Nevertheless, there are many doubts from a pharmacokinetic point of view that combination therapy of CLR with RIF might really be superior to other eradication protocols as suggested by the results of a retrospective clinical study in foals (Giguère et al, 2004). The absence of major drug interactions as shown in our recent pharmacokinetic study with tulathromycin and RIF should be confirmed before a combination treatment is launched in clinical practice (Venner et al, 2010).…”

“…To measure drug distribution in the ELF and BALC, a bronchoalveolar lavage was performed 12 h after the last administrations of CLR of each study period as described recently (Venner et al, 2010). In brief, after anesthesia with ketamine (Serumwerke, Bernburg, Germany) and diazepam (CT Arzneimittel, Berlin, Germany), a flexible fiberscope (Karl Storz, Tuttlingen, Germany) was advanced through the nose into the trachea to take two biopsy specimens from the bronchial epithelium behind the carina.…”

“…The efflux carriers ABCB1 and ABCC2 and several OATPs are modulated in the presence of RIF (Geick et al, 2001;Vavricka et al, 2002) After chronic treatment, however, RIF can up-regulate gene expression of intestinal and hepatic CYP3A4, ABCB1, ABCC2, and OAP1A2 via the nuclear pregnane X receptor (PXR) pathway (Vavricka et al, 2002;Zong and Pollack, 2003;Lau et al, 2006;Tirona, 2011). We have recently shown that RIF may also regulate pulmonary ABCB1 and ABCC2 of healthy foals (Venner et al, 2010). Therefore, the overall changes in absorption and pulmonary distribution of CRL may be caused by competitive effects in the presence of RIF and by the chronic effects as caused by PXR-type transporter induction.…”

A Novel Cell-Associated Protection Assay Demonstrates the Ability of Certain Antibiotics To Protect Ocular Surface Cell Lines from Subsequent Clinical Staphylococcus aureus Challenge

“…For example, when AZMresistant bacterial strain B1382 (MIC ϭ 64 g/ml) was used, no tested concentration of AZM was able to protect Chang or HCLE cells from the bacteria ( Fig. 1 and 2; see also rophages (8,13,21,22). The ability of these drugs to penetrate cells may be important in fighting obligate intracellular pathogens (2).…”

Efficacy of Tulathromycin for the Treatment of Foals with Mild to Moderate Bronchopneumonia

“…Intramuscular administration of TUL to healthy foals at a dosage of 2.5 mg/kg was well tolerated and resulted in drug concentrations in pulmonary epithelial lining fluid and bronchoalveolar cells considerably above concurrent plasma concentrations 10, 11. In a prospective study, 36 of 37 foals with small ultrasonographic pulmonary lesions (abscess score of 1.5 to 4.4 cm) treated with IM TUL once a week responded to therapy suggesting that the drug might be effective for the treatment of bronchopneumonia in foals 6.…”