A Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-Hepatocellular Carcinoma Compound 4-<i>N</i>-Carbobenzoxy-gemcitabine (Cbz-dFdC)
Gemcitabine (dFdC) demonstrates significant effectiveness against solid tumors in vitro and in vivo; however, its clinical application is limited because it tends to easily undergo deamination metabolism. Therefore, we synthesized 4-<i>N</i>-carbobenzoxy-gemcitabine (Cbz-dFdC) as a lead...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-05-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/25/9/2218 |
| _version_ | 1827717234188877824 |
|---|---|
| author | Yilin Sun Jiankun Wang Kun Hao |
| author_facet | Yilin Sun Jiankun Wang Kun Hao |
| author_sort | Yilin Sun |
| collection | DOAJ |
| description | Gemcitabine (dFdC) demonstrates significant effectiveness against solid tumors in vitro and in vivo; however, its clinical application is limited because it tends to easily undergo deamination metabolism. Therefore, we synthesized 4-<i>N</i>-carbobenzoxy-gemcitabine (Cbz-dFdC) as a lead prodrug and conducted a detailed pharmacokinetic, metabolic, and pharmacodynamic evaluation. After intragastric Cbz-dFdC administration, the C<sub>max</sub> of Cbz-dFdC and dFdC was 451.1 ± 106.7 and 1656.3 ± 431.5 ng/mL, respectively. The T<sub>max</sub> of Cbz-dFdC and dFdC was 2 and 4 h, respectively. After intragastric administration of Cbz-dFdC, this compound was mainly distributed in the intestine due to low carboxylesterase-1 (CES1) activity. Cbz-dFdC is activated by CES1 in both humans and rats. The enzyme kinetic curves were well fitted by the Michaelis–Menten equation in rats’ blood, plasma, and tissue homogenates and S9 of the liver and kidney, as well as human liver S9 and CES1 recombinase. The pharmacodynamic results showed that the Cbz-dFdC have a good antitumor effect in the HepG2 cell and in tumor-bearing mice, respectively. In general, Cbz-dFdC has good pharmaceutical characteristics and is therefore a good candidate for a potential prodrug. |
| first_indexed | 2024-03-10T19:57:38Z |
| format | Article |
| id | doaj.art-9b3d3960784e4fca95b1e43c8aa8adc8 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T19:57:38Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-9b3d3960784e4fca95b1e43c8aa8adc82023-11-19T23:51:56ZengMDPI AGMolecules1420-30492020-05-01259221810.3390/molecules25092218A Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-Hepatocellular Carcinoma Compound 4-<i>N</i>-Carbobenzoxy-gemcitabine (Cbz-dFdC)Yilin Sun0Jiankun Wang1Kun Hao2Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, ChinaLaboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, ChinaLaboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, ChinaGemcitabine (dFdC) demonstrates significant effectiveness against solid tumors in vitro and in vivo; however, its clinical application is limited because it tends to easily undergo deamination metabolism. Therefore, we synthesized 4-<i>N</i>-carbobenzoxy-gemcitabine (Cbz-dFdC) as a lead prodrug and conducted a detailed pharmacokinetic, metabolic, and pharmacodynamic evaluation. After intragastric Cbz-dFdC administration, the C<sub>max</sub> of Cbz-dFdC and dFdC was 451.1 ± 106.7 and 1656.3 ± 431.5 ng/mL, respectively. The T<sub>max</sub> of Cbz-dFdC and dFdC was 2 and 4 h, respectively. After intragastric administration of Cbz-dFdC, this compound was mainly distributed in the intestine due to low carboxylesterase-1 (CES1) activity. Cbz-dFdC is activated by CES1 in both humans and rats. The enzyme kinetic curves were well fitted by the Michaelis–Menten equation in rats’ blood, plasma, and tissue homogenates and S9 of the liver and kidney, as well as human liver S9 and CES1 recombinase. The pharmacodynamic results showed that the Cbz-dFdC have a good antitumor effect in the HepG2 cell and in tumor-bearing mice, respectively. In general, Cbz-dFdC has good pharmaceutical characteristics and is therefore a good candidate for a potential prodrug.https://www.mdpi.com/1420-3049/25/9/22184-<i>N</i>-carbobenzoxy-gemcitabinepharmacokineticpharmacodynamicprodrugcarboxylesterase-1 |
| spellingShingle | Yilin Sun Jiankun Wang Kun Hao A Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-Hepatocellular Carcinoma Compound 4-<i>N</i>-Carbobenzoxy-gemcitabine (Cbz-dFdC) Molecules 4-<i>N</i>-carbobenzoxy-gemcitabine pharmacokinetic pharmacodynamic prodrug carboxylesterase-1 |
| title | A Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-Hepatocellular Carcinoma Compound 4-<i>N</i>-Carbobenzoxy-gemcitabine (Cbz-dFdC) |
| title_full | A Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-Hepatocellular Carcinoma Compound 4-<i>N</i>-Carbobenzoxy-gemcitabine (Cbz-dFdC) |
| title_fullStr | A Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-Hepatocellular Carcinoma Compound 4-<i>N</i>-Carbobenzoxy-gemcitabine (Cbz-dFdC) |
| title_full_unstemmed | A Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-Hepatocellular Carcinoma Compound 4-<i>N</i>-Carbobenzoxy-gemcitabine (Cbz-dFdC) |
| title_short | A Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-Hepatocellular Carcinoma Compound 4-<i>N</i>-Carbobenzoxy-gemcitabine (Cbz-dFdC) |
| title_sort | pharmacokinetic and pharmacodynamic evaluation of the anti hepatocellular carcinoma compound 4 i n i carbobenzoxy gemcitabine cbz dfdc |
| topic | 4-<i>N</i>-carbobenzoxy-gemcitabine pharmacokinetic pharmacodynamic prodrug carboxylesterase-1 |
| url | https://www.mdpi.com/1420-3049/25/9/2218 |
| work_keys_str_mv | AT yilinsun apharmacokineticandpharmacodynamicevaluationoftheantihepatocellularcarcinomacompound4inicarbobenzoxygemcitabinecbzdfdc AT jiankunwang apharmacokineticandpharmacodynamicevaluationoftheantihepatocellularcarcinomacompound4inicarbobenzoxygemcitabinecbzdfdc AT kunhao apharmacokineticandpharmacodynamicevaluationoftheantihepatocellularcarcinomacompound4inicarbobenzoxygemcitabinecbzdfdc AT yilinsun pharmacokineticandpharmacodynamicevaluationoftheantihepatocellularcarcinomacompound4inicarbobenzoxygemcitabinecbzdfdc AT jiankunwang pharmacokineticandpharmacodynamicevaluationoftheantihepatocellularcarcinomacompound4inicarbobenzoxygemcitabinecbzdfdc AT kunhao pharmacokineticandpharmacodynamicevaluationoftheantihepatocellularcarcinomacompound4inicarbobenzoxygemcitabinecbzdfdc |