Abstract
Purpose. Developing a validated HPLC-DAD method for simultaneous determination of posaconazole (PSZ) and vincristine (VCR) in rat plasma. Methods. PSZ, VCR, and itraconazole (ITZ) were extracted from 200 μL plasma using diethyl ether in the presence of 0.1 M sodium hydroxide solution. The organic layer was evaporated in vacuo and dried residue was reconstituted and injected through HC-C18 (4.6 × 250 mm, 5 μm) column. In the mobile phase, acetonitrile and 0.015 M potassium dihydrogen orthophosphate (30 : 70 to 80 : 20, linear gradient over 7 minutes) pumped at 1.5 mL/min. VCR and PSZ were measured at 220 and 262 nm, respectively. Two Sprague Dawley rats were orally dosed PSZ followed by iv dosing of VCR and serial blood sampling was performed. Results. VCR, PSZ, and ITZ were successfully separated within 11 min. Calibration curves were linear over the range of 50–5000 ng/mL for both drugs. The CV% and % error of the mean were ≤18% and limit of quantitation was 50 ng/mL for both drugs. Rat plasma concentrations of PSZ and VCR were simultaneously measured up to 72 h and their calculated pharmacokinetics parameters were comparable to the literature. Conclusion. The assay was validated as per ICH guidelines and is appropriate for pharmacokinetics drug-drug interaction studies.
Highlights
Vincristine (VCR) is a mitotic inhibitor antineoplastic agent that is used mainly in combination chemotherapy regimens for acute and chronic leukemia, lymphomas, including Hodgkin’s disease and non-Hodgkin’s lymphomas, and multiple myeloma [1]
We describe the first simple and reliable RP-HPLC with diode array detection procedure for the simultaneous determination of PSZ and VCR in rat plasma
This paper demonstrates an easy, rapid, sensitive HPLC assay for the simultaneous determination of VCR and PSZ in rat plasma
Summary
Vincristine (VCR) is a mitotic inhibitor antineoplastic agent that is used mainly in combination chemotherapy regimens for acute and chronic leukemia, lymphomas, including Hodgkin’s disease and non-Hodgkin’s lymphomas, and multiple myeloma [1]. PSZ is given for prophylaxis in patients who are at high risk for invasive fungal disease due to immunosuppression, such as haematopoietic stem cell transplant recipients with graft-versus-host disease, or those with haematological malignancies with prolonged neutropenia as a result of chemotherapy [1, 2]. The coadministration of azoles (as prophylaxis or treatment of fungal infections) and VCR has been shown to increase VCR neurotoxic effects due to the inhibition of cytochrome P450 (CYP) isoform 3A4, for which VCR is a substrate [2]. Those neurotoxic symptoms usually appear as constipation and peripheral neurotoxicity [3]. Few case reports have illustrated the possible exacerbation of VCR toxicity by coadministration of PSZ in children and young adults where fluctuations in level of consciousness and seizures have been observed [4]
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