Dasatinib is a multi-kinase inhibitor that potently inhibits Bcr-Abl, Src family and platelet-derived growth factor receptor kinases. Methotrexate is an antimetabolite and antifolate drug. Clinical trials utilizing a combination of dasatinib and methotrexate in patients with Philadelphia chromosome positive and/or Bcr-Abl positive acute lymphoblastic leukemia are currently ongoing. A need therefore exists to develop a sensitive analytical method for determination of dasatinib and methotrexate in plasma.To estimate methotrexate, dasatinib and its active metabolite N-deshydroxyethyl dasatinib simultaneously using liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) in Wistar rat plasma.The analytes were extracted by using liquid-liquid extraction procedure and separated on a reverse phase C18 column (50 mm×3 mm i.d., 4.6 µ) using methanol: 2 mM ammonium acetate buffer, pH 4.0 as mobile phase at a flow rate 1 mL/min in gradient mode. Selective reaction monitoring was performed using the transitions m/z 455.0>175.0, 488.1 > 401.0, 444.26>401.0, and 271.1>- 155.0 to quantify methotrexate, dasatinib, N-deshydroxyethyl dasatinib and tolbutamide respectively.The method was validated over the concentration range of 1-1 000 ng/mL and the lower limit of quantitation was 1 ng/mL. The recoveries from spiked control samples were > 79% for all analytes and internal standard Intra- and Interday accuracy and precision of validated method were within the acceptable limits of < 15% at all concentration.The quantitation method was successfully applied for simultaneous estimation of methotrexate, dasatinib and N- deshydroxyethyl dasatinib in a pharmacokinetic study in Wistar rats.
A sensitive and reliable high-performance liquid chromatography-mass spectrometry (LC-MS/MS) was developed and validated for simultaneous quantification IC87114, roflumilast (RFM), and its active metabolite roflumilast N-oxide (RFN) using tolbutamide as an internal standard. The analytes were extracted by using liquid-liquid extraction and separated on a reverse phase C(18) column (50 mm × 3 mm i.d., 4.6 µ) using methanol: 2 mM ammonium acetate buffer, pH 4.0 as mobile phase at a flow rate 1 mL/min in gradient mode. Selective reaction monitoring was performed using the transitions m/z 398.3 > 145.9, 403.1 >186.9, 419.1 > 187.0 and 271.1 > 155.0 to quantify quantification IC87114, RFM, RFN and tolbutamide, respectively. The method was validated over the concentration range of 0.1-60 ng.mL(-1) for RFM and RFN and 6 to 2980 ng.mL(-1) for IC87114. Intra- and inter-day accuracy and precision of validated method were within the acceptable limits of <15% at all concentrations. Coefficients of correlation (r(2) ) for the calibration curves were >0.99 for all analytes. The quantitation method was successfully applied for simultaneous estimation of IC87114, RFM and RFN in a pharmacokinetic drug-drug interaction study in Wistar rats.
A new method for the simultaneous determination of celecoxib, erlotinib, and its active metabolite desmethyl-erlotinib (OSI-420) in rat plasma, by liquid chromatography/tandem mass spectrometry with positive/negative ion-switching electrospray ionization mode, was developed and validated. Protein precipitation with methanol was selected as the method for preparing the samples. The analytes were separated on a reverse-phase C18 column (50mm×4.6mm i.d., 3μ) using methanol: 2 mM ammonium acetate buffer, and pH 4.0 as the mobile phase at a flow rate 0.8 mL/min. Sitagliptin and Efervirenz were used as the internal standards for quantification. The determination was carried out on a Theremo Finnigan Quantam ultra triple-quadrupole mass spectrometer, operated in selected reaction monitoring (SRM) mode using the following transitions monitored simultaneously: positive m/z 394.5→278.1 for erlotinib, m/z 380.3→278.1 for desmethyl erlotinib (OSI-420), and negative m/z −380.1→ −316.3 for celecoxib. The limits of quantification (LOQs) were 1.5 ng/mL for Celecoxib, erlotinib, and OSI-420. Within- and between-day accuracy and precision of the validated method were within the acceptable limits of < 15% at all concentrations. The quantitation method was successfully applied for the simultaneous estimation of celecoxib, erlotinib, and desmethyl erlotinib in a pharmacokinetic study in Wistar rats.
Multi-dose administration of CLZ influences the pharmacokinetics and lipid-lowering properties of ATV. Collectively, an apparent interaction between selected drugs was evident.
Cilostazol (CLZ) and atorvastatin (ATV) are often co-prescribed to treat conditions such as peripheral arterial disease. In the present study, the drug-drug interaction potential of multi-dose ATV co-administration with CLZ on both pharmacokinetics and the anti-thrombotic property of CLZ is demonstrated. The pharmacokinetic parameters of CLZ (6 mg/kg, twice daily) were determined in male Wistar rats after 7 days co-administration with ATV (5 mg/kg, once daily) in order to assess the interaction potential between CLZ and ATV on chronic treatment. In vitro metabolic inhibition and everted gut sac studies were conducted to elucidate the mechanism of this interaction. Pharmacodynamic drug-drug interaction was evaluated on anti-thrombotic models including time to occlusion, platelet aggregation and rat tail bleeding time. A validated LC-MS/MS method was employed simultaneously to quantify both ATV and CLZ in rat plasma matrix. A statistically significant increase in systemic exposure (Css(max) by ~1.75 fold; AUC by ~3.0 fold) to CLZ was observed in ATV pre-treated rats. In vitro metabolism studies using liver microsomes (RLM and HLM) demonstrated statistically significant inhibition of CLZ metabolism when co-incubated with ATV. No change in apparent permeability of CLZ was observed in the presence of ATV. Atorvastatin showed a significant delay in artery occlusion time without altering CLZ's bleeding time and platelet aggregation profile. Collectively the results of these studies provide metabolic insight into the nature of drug-drug interaction between the selected drugs. Co-administration with ATV influences the pharmacokinetics and anti-thrombotic property of CLZ. A thorough clinical investigation is required before extrapolation of data to humans.
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