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Clartihromycin and ranitidine are accepted probe inhibitors in drug/drug interaction studies (DDI) with substrates of the multidrug transporters P-glycoprotein and OCT1. We assayed both drugs in human plasma, urine, and feces using LC–MS/MS with positive mass transition mode (AB Sciex API 2000 with turbo-ion spray) with fexofenadine as an internal standard. After protein denaturation with acetonitrile/water (50:50, v/v), the samples were centrifuged and the supernatants (10 µL) were injected into the chromatographic system (column: Supelco Ascentis® C18, 3 µm, 2.1 × 100 mm). The chromatography was performed with isocratic elution plied using ammonium formate buffer [(5 mM; pH 3.0)/acetonitrile, 40:60, v/v] as mobile phase at a flow rate of 200 μL min−1. The chromatograms were evaluated online with the internal standard method using peak-area-ratios for linear regression analysis weighted by 1/x (x = concentration) for the validation ranges in plasma between 0.005 and 2.0 µg mL−1, and for urine and feces between 0.005 and 10.0 µg mL−1. The method was shown to possess sufficient specificity, accuracy, precision and stability without matrix effects, thereby fulfilling current bioanalytical guidelines. The assay was suitable to simultaneous quantitative analysis of clarithromycin and ranitidine in plasma, urine, and feces of a DDI with trospium chloride to exclude major influence of trospium on the pharmacokinetics of the probe inhibitors. The assay is superior to other methods as it enables for the first time, quantification of the drugs in feces. [ABSTRACT FROM AUTHOR]

Intramuscular injection of diclofenac is still frequently practiced, although there is ample evidence that the risk of local tissue intolerability is highly underestimated. The aim of this study was to evaluate local toxicity in a patient using magnetic resonance imaging. A patient who gave written informed consent received a medically indicated intramuscular administration of diclofenac 75 mg/2 mL. Simultaneously with magnetic resonance imaging of the depot, a clinical-chemical evaluation and quantification of diclofenac in plasma was performed. A manifold enhancement of the T2-weighted magnetic resonance signal was observed in a muscle area of approximately 60 mL volume, with maximum signal intensity 30 min after injection, the time of maximum diclofenac plasma exposure. Plasma creatine kinase activity was elevated approximately sixfold within 8 h and normalized within 1 week, whereas the magnetic resonance enhancement disappeared within 5 weeks. Interestingly, the patient did not complain about any clinical symptoms at the injection site. Asymptomatic tissue injury after intramuscular injection of diclofenac, caused by intramuscular dosing, can be reliably evaluated by magnetic resonance imaging and should be applied early during the development of parenteral dosage forms. Clinical Trials Registration Number: BB130/16 (Ethics Committee of the University Medicine Greifswald). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]