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    The development and validation of assay methods for the quantitative determination of drugs and their metabolites in biological specimens: clarithromycin, carbamazepine and carbamazepine-10, 11-epoxide

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    Date
    2003-05
    Author
    Van Rooyen, Gert Frederick
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    Abstract
    The projects described in this dissertation use cutting edge technology to quantitate various drugs in plasma. Highly sensitive assay methods for the quantification of clarithromycin, carbamazepine and its major metabolite, carbamazepine-l0, Il-epoxide in human plasma were developed and validated. The application of these methods to analyse samples generated during pharmacokinetic studies is also discussed where up to 230 samples were analysed per day. The methods were sensitive enough to quantitate the analytes for at least 5 half-lives of the drug after an oral dose to human volunteers. A sensitive method for the determination of clarithromycin, a macrolide antibiotic, USing high-performance liquid chromatographic separation with tandem mass spectrometry, and the method development thereof, are described in this dissertation. Samples were prepared using liquid-liquid extraction and were separated on a CI8 column with a mobile phase consisting of acetonitrile, methanol and acetic acid. Detection was performed by a mass speetrometer in the multiple reaction monitoring (MRM) mode, using TurboIonSpray ionisation. The mean recovery of clarithromycin was 87.3%, with a lower limit of quantification of 2.95 ng/ml when using 300f!1 plasma. This high-throughput method was used to quantify 230 samples per day, and is sufficiently sensitive to be employed in pharmacokinetic studies. Carbamazepine, an anticonvulsant, and its major metabolite, carbamazepine-10, l l-epóxide, were quantified using tandem liquid chromatography-mass spectrometry, with electrospray ionisation. Both these analytes were extracted from 500f!1 of human plasma, using a liquid-liquid extraction method that showed recoveries greater than 95% for both these analytes. Concentrations as low as 0.722 ng/ml for carbamazepine and 5.15 ng/ml for carbamazepine-10, 11- epoxide could be quantified by using this method. These are the first LC-MSIMS assay methods described for the quantification of carbamazepine and its metabolite, carbamazepine-10, ll-epoxideas well as clarithromycin and their applications to pharmacokinetic studies.
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    http://hdl.handle.net/11660/6218
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