In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomes
TM208 and TM209, dithiocarbamate derivatives with potential anti-cancer effects, were evaluated in reversible and time-dependent cytochrome P450 (CYP) 3A inhibition assays in rat liver microsomes using testosterone as probe substrate. Both compounds were found to be weak reversible inhibitors and mo...
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| Format: | Article |
| Language: | English |
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Elsevier
2012-04-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383512000238 |
| _version_ | 1828324033230274560 |
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| author | Miaoran Ning Liang Li Jian Li Zaiquan Li Runtao Li Tianyan Zhou Wei Lu |
| author_facet | Miaoran Ning Liang Li Jian Li Zaiquan Li Runtao Li Tianyan Zhou Wei Lu |
| author_sort | Miaoran Ning |
| collection | DOAJ |
| description | TM208 and TM209, dithiocarbamate derivatives with potential anti-cancer effects, were evaluated in reversible and time-dependent cytochrome P450 (CYP) 3A inhibition assays in rat liver microsomes using testosterone as probe substrate. Both compounds were found to be weak reversible inhibitors and moderate mechanism-based inhibitors of rat CYP3A. For reversible inhibition on rat CYP3A, the Ki values of competitive inhibition model were 12.10±1.75 and 13.94±1.31 μM, respectively. For time-dependent inhibition, the inactivation constants (Kl) were 31.93±12.64 and 32.91±15.58 μM, respectively, and the maximum inactivation rates (kinact) were 0.03497±0.0069 and 0.07259±0.0172 min−1 respectively. These findings would provide useful in vitro information for future in vivo DDI studies on TM208 or TM209. |
| first_indexed | 2024-04-13T18:59:51Z |
| format | Article |
| id | doaj.art-0d723d23563344068ec9dc74e8a6cc28 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 2211-3843 |
| language | English |
| last_indexed | 2024-04-13T18:59:51Z |
| publishDate | 2012-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-0d723d23563344068ec9dc74e8a6cc282022-12-22T02:34:07ZengElsevierActa Pharmaceutica Sinica B2211-38352211-38432012-04-012218118710.1016/j.apsb.2012.02.006In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomesMiaoran Ning0Liang Li1Jian Li2Zaiquan Li3Runtao Li4Tianyan Zhou5Wei Lu6Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, ChinaDepartment of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, ChinaDepartment of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, ChinaDepartment of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, ChinaState Key Laboratory of Natural and Biomimetic Drugs (Peking University), Beijing 100191, ChinaState Key Laboratory of Natural and Biomimetic Drugs (Peking University), Beijing 100191, ChinaState Key Laboratory of Natural and Biomimetic Drugs (Peking University), Beijing 100191, ChinaTM208 and TM209, dithiocarbamate derivatives with potential anti-cancer effects, were evaluated in reversible and time-dependent cytochrome P450 (CYP) 3A inhibition assays in rat liver microsomes using testosterone as probe substrate. Both compounds were found to be weak reversible inhibitors and moderate mechanism-based inhibitors of rat CYP3A. For reversible inhibition on rat CYP3A, the Ki values of competitive inhibition model were 12.10±1.75 and 13.94±1.31 μM, respectively. For time-dependent inhibition, the inactivation constants (Kl) were 31.93±12.64 and 32.91±15.58 μM, respectively, and the maximum inactivation rates (kinact) were 0.03497±0.0069 and 0.07259±0.0172 min−1 respectively. These findings would provide useful in vitro information for future in vivo DDI studies on TM208 or TM209.http://www.sciencedirect.com/science/article/pii/S2211383512000238TM208TM209RLMsCYP3AReversible inhibitionTDIDDI |
| spellingShingle | Miaoran Ning Liang Li Jian Li Zaiquan Li Runtao Li Tianyan Zhou Wei Lu In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomes Acta Pharmaceutica Sinica B TM208 TM209 RLMs CYP3A Reversible inhibition TDI DDI |
| title | In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomes |
| title_full | In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomes |
| title_fullStr | In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomes |
| title_full_unstemmed | In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomes |
| title_short | In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomes |
| title_sort | in vitro screening of reversible and time dependent inhibition on cyp3a by tm208 and tm209 in rat liver microsomes |
| topic | TM208 TM209 RLMs CYP3A Reversible inhibition TDI DDI |
| url | http://www.sciencedirect.com/science/article/pii/S2211383512000238 |
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