The development and validation of an LC-MS/MS method for the determination of a new anti-malarial compound (TK900D) in human whole blood and its application to pharmacokinetic studies in mice
| dc.contributor.author | Abay, Efrem T | |
| dc.contributor.author | van der Westhuizen, Jan H | |
| dc.contributor.author | Swart, Kenneth J | |
| dc.contributor.author | Gibhard, Liezl | |
| dc.contributor.author | Tukulula, Matshawandile | |
| dc.contributor.author | Chibale, Kelly | |
| dc.contributor.author | Wiesner, Lubbe | |
| dc.date.accessioned | 2015-07-30T03:59:33Z | |
| dc.date.available | 2015-07-30T03:59:33Z | |
| dc.date.issued | 2014-01-31 | |
| dc.date.updated | 2015-01-15T17:55:30Z | |
| dc.description.abstract | Abstract Background Malaria is one of the most lethal and life-threatening killer infectious diseases in the world, and account for the deaths of more than half a million people annually. Despite the remarkable achievement made in preventing and eradicating malaria, it still remains a threat to the public health and a burden to the global economy due to the emergence of multiple-drug resistant malaria parasites. Therefore, the need to develop new anti-malarial drugs is crucial. The chemistry department at the University of Cape Town synthesized a number of new CQ-like derivatives (TK-series), and evaluated them for in vitro activity against both CQ-sensitive and -resistant Plasmodium falciparum strains, and for general cytotoxicity against a Chinese Hamster Ovarian (CHO) mammalian cell line. The lead compounds from the TK-series were selected for a comprehensive pharmacokinetic (PK) evaluation in a mouse model. Methods A sensitive LC-MS/MS assay was developed for the quantitative determination of TK900D. Multiple reaction monitoring (MRM) in the positive ionization mode was used for detection. The analyte and the internal standard (TK900E) were isolated from blood samples by liquid-liquid extraction with ethyl acetate. Chromatographic separation was achieved with a Phenomenex® Kinetex C18 (100 × 2.0 mm id, 2.6 μm) analytical column, using a mixture of 0.1% formic acid and acetonitrile (50:50; v/v) as the mobile phase. The method was fully validated over concentrations that ranged from 3.910 to 1000 ng/ml, and used to evaluate the PK properties of the lead compounds in a mouse model. Results The assay was robust, with deviation not exceeding 11% for the intra- and inter-run precision and accuracy. Extraction recovery was consistent and more than 60%. PK evaluation showed that TK900D and TK900E have moderate oral bioavailability of 30.8% and 25.9%, respectively. The apparent half-life ranged between 4 to 6 h for TK900D and 3.6 to 4 h for TK900E. Conclusion The assay was sensitive and able to measure accurately low drug levels from a small sample volume (20 μl). PK evaluation showed that the oral bioavailability was moderate. Therefore, from a PK perspective, the compounds look promising and can be taken further in the drug development process. | |
| dc.identifier.apacitation | Abay, E. T., van der Westhuizen, J. H., Swart, K. J., Gibhard, L., Tukulula, M., Chibale, K., & Wiesner, L. (2014). The development and validation of an LC-MS/MS method for the determination of a new anti-malarial compound (TK900D) in human whole blood and its application to pharmacokinetic studies in mice. <i>Malaria Journal</i>, http://hdl.handle.net/11427/13606 | en_ZA |
| dc.identifier.chicagocitation | Abay, Efrem T, Jan H van der Westhuizen, Kenneth J Swart, Liezl Gibhard, Matshawandile Tukulula, Kelly Chibale, and Lubbe Wiesner "The development and validation of an LC-MS/MS method for the determination of a new anti-malarial compound (TK900D) in human whole blood and its application to pharmacokinetic studies in mice." <i>Malaria Journal</i> (2014) http://hdl.handle.net/11427/13606 | en_ZA |
| dc.identifier.citation | Abay, E. T., van der Westhuizen, J. H., Swart, K. J., Gibhard, L., Tukulula, M., Chibale, K., & Wiesner, L. (2014). The development and validation of an LC-MS/MS method for the determination of a new anti-malarial compound (TK900D) in human whole blood and its application to pharmacokinetic studies in mice. Malaria journal, 13(1), 42. | |
| dc.identifier.ris | TY - Journal Article AU - Abay, Efrem T AU - van der Westhuizen, Jan H AU - Swart, Kenneth J AU - Gibhard, Liezl AU - Tukulula, Matshawandile AU - Chibale, Kelly AU - Wiesner, Lubbe AB - Abstract Background Malaria is one of the most lethal and life-threatening killer infectious diseases in the world, and account for the deaths of more than half a million people annually. Despite the remarkable achievement made in preventing and eradicating malaria, it still remains a threat to the public health and a burden to the global economy due to the emergence of multiple-drug resistant malaria parasites. Therefore, the need to develop new anti-malarial drugs is crucial. The chemistry department at the University of Cape Town synthesized a number of new CQ-like derivatives (TK-series), and evaluated them for in vitro activity against both CQ-sensitive and -resistant Plasmodium falciparum strains, and for general cytotoxicity against a Chinese Hamster Ovarian (CHO) mammalian cell line. The lead compounds from the TK-series were selected for a comprehensive pharmacokinetic (PK) evaluation in a mouse model. Methods A sensitive LC-MS/MS assay was developed for the quantitative determination of TK900D. Multiple reaction monitoring (MRM) in the positive ionization mode was used for detection. The analyte and the internal standard (TK900E) were isolated from blood samples by liquid-liquid extraction with ethyl acetate. Chromatographic separation was achieved with a Phenomenex® Kinetex C18 (100 × 2.0 mm id, 2.6 μm) analytical column, using a mixture of 0.1% formic acid and acetonitrile (50:50; v/v) as the mobile phase. The method was fully validated over concentrations that ranged from 3.910 to 1000 ng/ml, and used to evaluate the PK properties of the lead compounds in a mouse model. Results The assay was robust, with deviation not exceeding 11% for the intra- and inter-run precision and accuracy. Extraction recovery was consistent and more than 60%. PK evaluation showed that TK900D and TK900E have moderate oral bioavailability of 30.8% and 25.9%, respectively. The apparent half-life ranged between 4 to 6 h for TK900D and 3.6 to 4 h for TK900E. Conclusion The assay was sensitive and able to measure accurately low drug levels from a small sample volume (20 μl). PK evaluation showed that the oral bioavailability was moderate. Therefore, from a PK perspective, the compounds look promising and can be taken further in the drug development process. DA - 2014-01-31 DB - OpenUCT DO - 10.1186/1475-2875-13-42 DP - University of Cape Town J1 - Malaria Journal LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - The development and validation of an LC-MS/MS method for the determination of a new anti-malarial compound (TK900D) in human whole blood and its application to pharmacokinetic studies in mice TI - The development and validation of an LC-MS/MS method for the determination of a new anti-malarial compound (TK900D) in human whole blood and its application to pharmacokinetic studies in mice UR - http://hdl.handle.net/11427/13606 ER - | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/11427/13606 | |
| dc.identifier.uri | http://dx.doi.org/10.1186/1475-2875-13-42 | |
| dc.identifier.vancouvercitation | Abay ET, van der Westhuizen JH, Swart KJ, Gibhard L, Tukulula M, Chibale K, et al. The development and validation of an LC-MS/MS method for the determination of a new anti-malarial compound (TK900D) in human whole blood and its application to pharmacokinetic studies in mice. Malaria Journal. 2014; http://hdl.handle.net/11427/13606. | en_ZA |
| dc.language.rfc3066 | en | |
| dc.publisher.department | Division of Clinical Pharmacology | en_ZA |
| dc.publisher.faculty | Faculty of Health Sciences | en_ZA |
| dc.publisher.institution | University of Cape Town | |
| dc.rights | This is an open access article distributed under the terms of the Creative Commons Attribution License | * |
| dc.rights.holder | Abay et al.; licensee BioMed Central Ltd. | |
| dc.rights.uri | http://creativecommons.org/licenses/by/2.0 | * |
| dc.source | Malaria Journal | en_ZA |
| dc.source.uri | http://www.malariajournal.com | |
| dc.subject.other | Malaria | en_ZA |
| dc.subject.other | Drug development | en_ZA |
| dc.subject.other | Pharmacokinetics | en_ZA |
| dc.title | The development and validation of an LC-MS/MS method for the determination of a new anti-malarial compound (TK900D) in human whole blood and its application to pharmacokinetic studies in mice | |
| dc.type | Journal Article | en_ZA |
| uct.type.filetype | ||
| uct.type.filetype | Text | |
| uct.type.filetype | Image | |
| uct.type.publication | Research | en_ZA |
| uct.type.resource | Article | en_ZA |