Please use this identifier to cite or link to this item: https://www.um.edu.mt/library/oar/handle/123456789/42361
Title: Pulmonary and general pharmacokinetic studies on racemic ethosuximide using a chiral sensitive GC/MS technique.
Authors: Sghendo, Lino
Keywords: Pharmacokinetics
Anticonvulsants
Gas chromatography
Issue Date: 2002
Citation: Sghendo, L. (2002). Pulmonary and general pharmacokinetic studies on racemic ethosuximide using a chiral sensitive GC/MS technique (Master's dissertation).
Abstract: A modified specific, sensitive and reproducible chiral gas chromatographic method for the resolution and quantification of ethosuximide enantiomers in urine and plasma was developed. The samples were extracted by liquid-liquid extraction, using diethylether and the enantiomers were separated and quantified on a chiral gas chromatographic column. The method involved the use of GC/MS instrumentation for the acquisition of data in the electron impact, selective-ion monitoring mode, collecting ions of mass-to-charge ratio (mlz) exactly equal to 55 and 70 units and which were specific for ethosuximide. The limit of quantitation of the method was 5 µg/ml for urine samples and 10 µg/ml for plasma samples with both enantiomers. The method proved to be linear, precise and reproducible in the 5-300 µg/ml concentration range for urine samples and in the 10-250 µg/ml concentration range for plasma samples. Intraday and interday coefficients of variation were low, while recovery studies were acceptable. The reproducible extraction and quantification techniques were applied in the determination of pulmonary pharmacokinetic parameters of the enantiomers following the intravenous administration of rac-ethosuximide to an intact rabbit model. Following a 6 mg intravenous bolus dose of rac-ethosuximide to New Zealand white rabbits, (S)-ethosuximide had a mean (± standard deviation) pulmonary uptake of 39.15 ± 13.38% and a mean retention of 63.49 ± 8.03%, while (R)-ethosuximide had a mean pulmonary uptake of 24.18 ± 16.93% and a mean retention of 54.51 ± 10.16%. Also, following the first-pass of indocyanine green dye, a nonextractable indicator, through lung tissue, mean transit time was equal to 13.535 ± 0.010 s, cardiac output was equal to 280.67 ± 49.69 mlmin-1 , while central blood volume was equal to 63.31 ± 11.21 ml. The chiral GC/MS method developed was also applied in the determination of general pharrnacokinetic parameters of ethosuximide following the intravenous administration of different doses of the drug to rats. Statistically significant differences were found for half-life and clearance of the enantiomers of ethosuximide (p < 0.05). After a 40 mg intravenous bolus dose of rac-ethosuximide, (S)ethosuximide had a mean (± standard deviation) half-life of 23.5 (± 1.6) h and a clearance of 0.064 (± 0.022) Lh-1kg-1, while (R)-ethosuximide had a mean half-life of 19.4 (± 1.2) h and a clearance of 0.067 (± 0.045) Lh-1kg-1. No statistically significant difference was found for volume of distribution estimated for both enantiomers (2.184 ± 0.791 Lkg-1 for (S)-ethosuximide and 1.843 ± 1.166 Lkg-1 for (R)-ethosuximide) (p > 0.05).
Description: M.SC.PHARMACOLOGY
URI: https://www.um.edu.mt/library/oar//handle/123456789/42361
Appears in Collections:Dissertations - FacM&S - 2002
Dissertations - FacM&SCPT - 2002



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