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Ultraviolet and Light Absorption Spectrometry
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Zoltan M. Dinya, Ferenc J. Sztaricskai
The European Pharmacopoeia [139] and the British Pharmacopoeia 1980 [13] specify a colorimetric method for streptomycin sulfate, as well as the micro-biological turbidimetric procedure. The National Formulary allows a spectrophotometric method for troleandomycin [15].
In vitro drug–drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes
Published in Xenobiotica, 2018
Nancy Chen, Donghui Cui, Qing Wang, Zhiming Wen, Richard D. Finkelman, Devin Welty
Co-administration of oral budesonide (10 mg, single dose) with oral ketoconazole (a known inhibitor of CYP3A; 100 mg, twice daily) has been shown to lead to an eightfold increase in systemic budesonide exposure (US Food and Drug Administration, 2009). Furthermore, co-administration of oral budesonide (4 mg, single dose) with cimetidine (a potent inhibitor of CYP3A4; 1 g daily) resulted in a 52% and a 31% increase in budesonide peak plasma concentration and area under the curve, respectively (US Food and Drug Administration, 2009). In vitro co-incubation of human liver microsomes (HLM) with budesonide and ketoconazole resulted in the in vitro inhibition of budesonide metabolism (concentration of inhibitor at 50% inhibition [IC50] ∼ 0.1 μM) (Jonsson et al., 1995). This effect was also observed with other known inhibitors of CYP3A family enzymes, including troleandomycin, erythromycin and cyclosporine with respective IC50 values of ∼1 μM, ∼100 μM and ∼100 μM (Jonsson et al., 1995). With this knowledge, a reduction of budesonide dose may need to be considered if concomitant treatment with known inhibitors of CYP3A is indicated.
Numerical analysis of time-dependent inhibition kinetics: comparison between rat liver microsomes and rat hepatocyte data for mechanistic model fitting
Published in Xenobiotica, 2020
Chuong Pham, Swati Nagar, Ken Korzekwa
Incubations to assess TDI were completed in two parts. The primary incubation contained the CYP3A inhibitor troleandomycin (TAO) at a final concentration of 0, 0.5, 1, 2, 4 or 8 μM in 0.1% ACN, 0.5 mg/mL microsomes and NADPH regenerating system in 0.1 M phosphate buffer. Following incubation in microcentrifuge tubes for 0, 5, 15, 30 and 45 min in a 37 °C water bath with shaking at 40 RPM, an aliquot was diluted 20× into the secondary incubation with a final concentration of CYP3A substrate 100 μM midazolam (MDZ) in 0.1% ACN, and NADPH regenerating system in 0.1 M phosphate buffer. After 3 min at 37 °C with shaking at 40 RPM, the reactions were stopped with an equal volume of cold stop solution (50 ng/mL diltiazem internal standard (IS) in ACN).
Metabolism of megestrol acetate in vitro and the role of oxidative metabolites
Published in Xenobiotica, 2018
Larry House, Michael J. Seminerio, Snezana Mirkov, Jacqueline Ramirez, Maxwell Skor, Joseph R. Sachleben, Masis Isikbay, Hari Singhal, Geoffrey L. Greene, Donald Vander Griend, Suzanne D. Conzen, Mark J. Ratain
Formation of metabolites from MA (28 and 62 µM) was evaluated in the absence (control) and presence of known CYP3A inhibitors. The inhibitors used were ketoconazole (1 µM) and troleandomycin (50 µM). After pre-incubating with ketoconazole (a potent competitive inhibitor), MA (62 µM) and NADPH for 15 min at 37 °C, the reaction was initiated by adding HLMs or CYP3A4. After pre-incubating HLMs or CYP3A4 with troleandomycin (a mechanism-based inactivator) and NADPH for 15 min at 37 °C, the reaction was started by adding MA (62 µM). The same experiment was performed using a substrate concentration of 28 µM for HLMs only. Negative controls for all reactions were in the absence of protein. All incubations were performed in triplicate.