Evaluation of the inhibition effects of apatinib on human and rat cytochrome P450

Bao, Su-su; Wen, Jian Ming; Xiang, Zheng; Zhou, Quan; Qu, Gao-er; Chen, Ming-jing; Hu, Guoxin

doi:10.1016/j.toxlet.2018.08.010

Cited by 15 publications

(16 citation statements)

References 38 publications

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“…Apatinib is confirmed as a strong inhibitor of CYP450s, [9] and buspirone is acknowledged as a substrate of CYP3A4. [25] .…”

Section: Discussionmentioning

confidence: 96%

“…The results showed apatinib affected buspirone by a mixed way both in N-dealkylating and in hydroxylating which is not different with the previous. [9] Additionally, to study whether apatinib had the same effect on buspirone in human, the inhibitory experiment was performed with HLM in vitro. Buspirone was inhibited by apatinib strongly in HLM.…”

Section: Discussionmentioning

confidence: 99%

“…[8] Interestingly, apatinib was also determined as an inhibitor of CYP450s in vitro previously. [9] Therefore, if combined apatinib with a drug that is mainly metabolized by CYP450s, an extra attention should be drawn to avoid adverse reactions caused by increased drug exposure in blood.…”

Section: Introductionmentioning

confidence: 99%

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The effect of apatinib on pharmacokinetic profile of buspirone both in vivo and in vitro

Zhang

Chen

et al. 2020

Journal of Pharmacy and Pharmacology

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Objective In this study, we aimed to investigate the potential interaction of apatinib and buspirone and underlying mechanism. Methods UPLC‐MS/MS assay was applied to determine the concentrations of buspirone and its main metabolites (1‐PP and 6‐OH buspirone) after incubated with liver microsomes. Moreover, the connection of in vitro and in vivo was further determined. Sprague Dawley rats were randomly divided into two groups: group A (20 mg/kg buspirone) and group B (buspirone vs 40 mg/kg apatinib). Tail vein blood was collected and subjected to the UPLC‐MS/MS detection. Key findings Apatinib inhibited the generations of 1‐PP and 6‐OH buspirone dose‐dependently with IC50 of 1.76 and 2.23 μm in RLMs, and 1.51 and 1.48 μm in HLMs, respectively. There was a mixed mechanism underlying such an inhibition effect. In rat, AUC(0–t), AUC(0–∞), Tmax and Cmax of buspirone and 6‐OH buspirone increased significantly while co‐administering with apatinib, but Vz/F and CLz/F decreased obviously while comparing group A with group B . Conclusions Apatinib suppresses the CYP450 based metabolism of buspirone in a mixed mechanism and boosted the blood exposure of prototype drug and 6‐OH buspirone dramatically. Therefore, extra caution should be taken when combining apatinib with buspirone in clinic.

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“…Apatinib is confirmed as a strong inhibitor of CYP450s, [9] and buspirone is acknowledged as a substrate of CYP3A4. [25] .…”

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The effect of apatinib on pharmacokinetic profile of buspirone both in vivo and in vitro

Zhang

Chen

et al. 2020

Journal of Pharmacy and Pharmacology

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“…Introduction Drug-drug interactions frequently occur in the clinic, causing adverse reactions, ineffective therapeutic outcomes, or boosted efficacy. Combinational treatment of traditional Chinese herb or Chinese patent medicine with chemical drugs is one of the primary reasons for such situations [1][2][3]. With the wide application of traditional Chinese medicine, the incidence of drug-drug interactions has risen sharply [4,5].…”

Section: Herbacetin Broadly Blocks the Activities Of Cyp450s By Different Inhibitory Mechanismsmentioning

confidence: 99%

Herbacetin Broadly Blocks the Activities of CYP450s by Different Inhibitory Mechanisms

Qian

Zhang

et al. 2021

Planta Med

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Herbacetin is a bioactive flavanol compound that has various pharmacological effects. However, the pharmacokinetic characteristics have not been thoroughly investigated. Previously, we screened a natural compound library and identified herbacetin as a potent CYP blocker. Herein, we aimed to mechanistically determine the inhibitory effects of herbacetin on CYP450 and its potential application. A human liver microsome incubation system was developed based on a UPLC-MS/MS method. Moreover, an in silico docking assay and a human CYP recombinase reaction system were developed and used to investigate binding affinity and inhibitory efficacy. Subsequently, the effects of the combination of herbacetin and sorafenib on HepG2 cells were assessed by MTT and immunoblotting assays. The concentration of sorafenib and its main metabolite were measured by UPLC-MS/MS after incubation with or without herbacetin. As a result, we found herbacetin almost completely inhibited the functions of major CYPs at 100 µM. Moreover, through analysis of the structure-activity relationship, we found 4-, 6-, and 8-hydroxyl were essential groups for the inhibitory effects. Herbacetin inhibited CYP3A4, CYP2B6, CYP2C9, and CYP2E1 in a mixed manner, but non-competitively blocked CYP2D6. These results are in good agreement with the recombinase reaction in vitro results, with an IC50 < 10 µM for each tested isoenzyme. Interestingly, the stimulatory effects of sorafenib on HepG2 cell apoptosis were significantly enhanced by combining with herbacetin, which was associated with increased sorafenib exposure. In summary, herbacetin is a potent inhibitor of a wide spectrum of CYP450s, which may enhance the exposure of drugs in vivo.

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“…The less selective of these inhibitors limited their clinical use. New-generation tyrosine kinase inhibitors (TKIs) include icotinib,14 apatinib,15 famitinib,16 flumatinb,17 allitinib,18 fruquintinib,19 and selatinib,20 among which icotinib and apatinib have been approved in China, while others are in clinical trials. Fruquintinib (6-(6, 7-dimethoxyquinazolin-4-yloxy) - N,2-dimethylbenzofuran-3-carboxamide, Figure 1A) developed by Hutchison MediPharma Ltd. (Shanghai, China) had been studied in Phase II and Phase III clinical trial for non-small-cell lung cancer (“NSCLC”) and colorectal cancer (CRC) and demonstrated highly potent efficacy and safety profile in vitro and in vivo 19,21–24.…”

Section: Introductionmentioning

confidence: 99%

<p>Validated UPLC-MS/MS method for quantification of fruquintinib in rat plasma and its application to pharmacokinetic study</p>

Mei

Luo

et al. 2019

DDDT

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A new, simple, and sensitive ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of fruquintinib was established to assess the pharmacokinetics of fruquintinib in the rat. The internal standard working solution was added to the plasma sample for extraction before analysis. The Acquity UPLC BEH C18 chromatography column (2.1 mm ×50 mm, 1.7 μm) was used to separated analytes under gradient elution using acetonitrile and 0.1% formic acid as the mobile phase. Positive multiple reaction monitoring modes were chosen to detect fruquintinib and diazepam (IS). The precursor-to-product ion transitions were 394.2 → 363.2 for fruquintinib and m/z 285 → 154 for IS. The current method was linear over the concentration range of 1.0–1000 ng/mL for fruquintinib with a correlation coefficient of 0.9992 or better. The matrix effect of fruquintinib and IS was acceptable under the current method. The intra- and interday precision (RSD%) and accuracy (RE%) were within 11.9% and ±13.7%, respectively. The recovery, stability, and sensitivity were validated according to the United States Food and Drug Administration (FDA) regulations for bioanalytical method validation. The analytical method had been validated and applied to a pharmacokinetic study of fruquintinib in rat.

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Evaluation of the inhibition effects of apatinib on human and rat cytochrome P450

Cited by 15 publications

References 38 publications

The effect of apatinib on pharmacokinetic profile of buspirone both in vivo and in vitro

The effect of apatinib on pharmacokinetic profile of buspirone both in vivo and in vitro

Herbacetin Broadly Blocks the Activities of CYP450s by Different Inhibitory Mechanisms

<p>Validated UPLC-MS/MS method for quantification of fruquintinib in rat plasma and its application to pharmacokinetic study</p>

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