Simultaneous Determination of A Novel Antitrypanosomal Compound (OSU-36) and its Ester Derivative (OSU-40) in Plasma by HPLC: Application to First Pharmacokinetic Study in Rats
Purpose. To develop an HPLC-UV method for determination of a novel antitrypanosomal compound (OSU-36) and its ester prodrug (OSU-40) in rat plasma and to apply the method for pharmacokinetic evaluation of both compounds in rats. Methods. Since an attempt to assay for OSU-36 and OSU-40 in non-stabili...
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Canadian Society for Pharmaceutical Sciences
2011-01-01
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doaj-a24d6a1d2567454d8da1cfd9620625a02020-11-25T04:06:04ZengCanadian Society for Pharmaceutical SciencesJournal of Pharmacy & Pharmaceutical Sciences1482-18262011-01-0114110.18433/J3CP4SSimultaneous Determination of A Novel Antitrypanosomal Compound (OSU-36) and its Ester Derivative (OSU-40) in Plasma by HPLC: Application to First Pharmacokinetic Study in RatsPavel Gershkovich0Kishor M. WasanOlena SivakSummer LysakowskiCarolyn ReidKokku PremalathaKarl A. WerbovetzUniversity of British ColumbiaPurpose. To develop an HPLC-UV method for determination of a novel antitrypanosomal compound (OSU-36) and its ester prodrug (OSU-40) in rat plasma and to apply the method for pharmacokinetic evaluation of both compounds in rats. Methods. Since an attempt to assay for OSU-36 and OSU-40 in non-stabilized plasma resulted in highly non-linear calibration curves and poor sensitivity due to instability of the compounds, the plasma was stabilized using paraoxon and ascorbic acid. The sample treatment included protein precipitation by acetonitrile; evaporation; reconstitution with acetonitrile and filtration. The chromatography conditions included Xterra RP18 3.5µm 4.6X100mm column and gradient mobile phase system of acetonitrile-water. Results. The limits of quantification (LOQ) were 50 ng/mL and 40 ng/mL for OSU-36 and OSU-40, respectively. The intra- and interday precision and accuracies were below 13% for low, medium and high quality control samples for both compounds. While OSU-40 has been stable in all tested handling conditions, OSU-36 was unstable in plasma after 20 days storage in -80°C or 4h 28°C storage. The developed method has been applied for a pharmacokinetic study in rats which revealed that an ester prodrug OSU-40 is rapidly converted to OSU-36 within the plasma compartment by plasma esterases. OSU-36, in turn, relatively quickly undergoes oxidative metabolism, including within the plasma compartment. Conclusions. A supplementation of rat plasma with an esterase inhibitor to prevent degradation of ester prodrug (OSU-40), and with antioxidant to prevent oxidation of OSU-36, is necessary for reliable determination of both compounds. Due to limited stability of OSU-36 in stabilized rat plasma, long-term storage of samples or prolonged handling in room temperature conditions is not recommended.https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/9374 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Pavel Gershkovich Kishor M. Wasan Olena Sivak Summer Lysakowski Carolyn Reid Kokku Premalatha Karl A. Werbovetz |
spellingShingle |
Pavel Gershkovich Kishor M. Wasan Olena Sivak Summer Lysakowski Carolyn Reid Kokku Premalatha Karl A. Werbovetz Simultaneous Determination of A Novel Antitrypanosomal Compound (OSU-36) and its Ester Derivative (OSU-40) in Plasma by HPLC: Application to First Pharmacokinetic Study in Rats Journal of Pharmacy & Pharmaceutical Sciences |
author_facet |
Pavel Gershkovich Kishor M. Wasan Olena Sivak Summer Lysakowski Carolyn Reid Kokku Premalatha Karl A. Werbovetz |
author_sort |
Pavel Gershkovich |
title |
Simultaneous Determination of A Novel Antitrypanosomal Compound (OSU-36) and its Ester Derivative (OSU-40) in Plasma by HPLC: Application to First Pharmacokinetic Study in Rats |
title_short |
Simultaneous Determination of A Novel Antitrypanosomal Compound (OSU-36) and its Ester Derivative (OSU-40) in Plasma by HPLC: Application to First Pharmacokinetic Study in Rats |
title_full |
Simultaneous Determination of A Novel Antitrypanosomal Compound (OSU-36) and its Ester Derivative (OSU-40) in Plasma by HPLC: Application to First Pharmacokinetic Study in Rats |
title_fullStr |
Simultaneous Determination of A Novel Antitrypanosomal Compound (OSU-36) and its Ester Derivative (OSU-40) in Plasma by HPLC: Application to First Pharmacokinetic Study in Rats |
title_full_unstemmed |
Simultaneous Determination of A Novel Antitrypanosomal Compound (OSU-36) and its Ester Derivative (OSU-40) in Plasma by HPLC: Application to First Pharmacokinetic Study in Rats |
title_sort |
simultaneous determination of a novel antitrypanosomal compound (osu-36) and its ester derivative (osu-40) in plasma by hplc: application to first pharmacokinetic study in rats |
publisher |
Canadian Society for Pharmaceutical Sciences |
series |
Journal of Pharmacy & Pharmaceutical Sciences |
issn |
1482-1826 |
publishDate |
2011-01-01 |
description |
Purpose. To develop an HPLC-UV method for determination of a novel antitrypanosomal compound (OSU-36) and its ester prodrug (OSU-40) in rat plasma and to apply the method for pharmacokinetic evaluation of both compounds in rats. Methods. Since an attempt to assay for OSU-36 and OSU-40 in non-stabilized plasma resulted in highly non-linear calibration curves and poor sensitivity due to instability of the compounds, the plasma was stabilized using paraoxon and ascorbic acid. The sample treatment included protein precipitation by acetonitrile; evaporation; reconstitution with acetonitrile and filtration. The chromatography conditions included Xterra RP18 3.5µm 4.6X100mm column and gradient mobile phase system of acetonitrile-water. Results. The limits of quantification (LOQ) were 50 ng/mL and 40 ng/mL for OSU-36 and OSU-40, respectively. The intra- and interday precision and accuracies were below 13% for low, medium and high quality control samples for both compounds. While OSU-40 has been stable in all tested handling conditions, OSU-36 was unstable in plasma after 20 days storage in -80°C or 4h 28°C storage. The developed method has been applied for a pharmacokinetic study in rats which revealed that an ester prodrug OSU-40 is rapidly converted to OSU-36 within the plasma compartment by plasma esterases. OSU-36, in turn, relatively quickly undergoes oxidative metabolism, including within the plasma compartment. Conclusions. A supplementation of rat plasma with an esterase inhibitor to prevent degradation of ester prodrug (OSU-40), and with antioxidant to prevent oxidation of OSU-36, is necessary for reliable determination of both compounds. Due to limited stability of OSU-36 in stabilized rat plasma, long-term storage of samples or prolonged handling in room temperature conditions is not recommended. |
url |
https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/9374 |
work_keys_str_mv |
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