The Effect of Apigenin on Pharmacokinetics of Imatinib and Its Metabolite N-Desmethyl Imatinib in Rats

Liu, Xianyun; Xu, Tao; Li, Wan-shu; Luo, Jun; Geng, Peiwu; Wang, Li; Xia, Meng-Ming; Chen, Mengchun; Yu, Lei; Hu, Guoxin

doi:10.1155/2013/789184

Cited by 13 publications

(18 citation statements)

References 24 publications

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“…Since silybin is subjected to CYP2C9-and CYP3A4-mediated metabolism (Sridar et al 2004), the decreased CL/F and increased AUC of etoposide suggests that the metabolism of imatinib in the liver might be inhibited. This study is consistent with the results reported by our previous research (Liu et al 2013). Apigenin, another flavonoid compound, significantly increased the AUC and reduced the CL/F after administered imatinib in rats at a single dose.…”

Section: Discussionsupporting

confidence: 93%

Inhibitory effect of silybin on pharmacokinetics of imatinib in vivo and in vitro

Wang

Xia

et al. 2014

Can. J. Physiol. Pharmacol.

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The objective of this work was to investigate the effect of orally administered silybin on the pharmacokinetics of imatinib in rats and the metabolism of imatinib in human liver microsome and rat liver microsomes. Eighteen healthy male SD rats were randomly divided into 3 groups: group A (control group), group B (received multiple doses of 50 mg·kg(-1) silybin for 15 consecutive days), and group C (received a single dose of 50 mg·kg(-1) silybin). A single dose of imatinib was administered orally 30 min after administration of silybin (50 mg·kg(-1)). Imatinib plasma levels were measured by UPLC-MS/MS, and pharmacokinetic parameters were calculated by DAS 3.0 software (Bontz Inc., Beijing, China). In addition, human and rat liver microsome were performed to determine the effects of silybin metabolism of imatinib in vitro. The multiple doses or single dose of 50 mg·kg(-1) silybin significantly decreased the area under the curve (0-t) of imatinib (p < 0.01). And the half-life (t1/2) of imatinib is significantly increased (p < 0.05 and p < 0.01, respectively). Also, silybin showed inhibitory effect on human and rat microsomes, the IC50 of silybin were 26.42 μmol·L(-1) and 49.12 μmol·L(-1) in human and rat liver microsomes, respectively. These results indicate that more attention should be paid to when imatinib is administrated combined with silybin.

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Section: Discussionsupporting

confidence: 93%

Inhibitory effect of silybin on pharmacokinetics of imatinib in vivo and in vitro

Wang

Xia

et al. 2014

Can. J. Physiol. Pharmacol.

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“…Furthermore, the presence of apigenin may be a contributing factor to improve the systemic exposure of other CYP2C9 substrates such as (S)-warfarin, tolbutamide, phenytoin, and acenocoumarol in vivo [19] . And our previous studies indicated that the coadministration in rat with apigenin could increase the absorption of imatinib and venlafaxine [29,30] . Meanwhile, further interaction investigations between apigenin and clinical drugs in vivo studies should be carried out.…”

Section: Discussionmentioning

confidence: 94%

Inhibitory Effect of Apigenin on Losartan Metabolism and CYP2C9 Activity in vitro

Wang

Gong²,

Zeng³

et al. 2016

Pharmacology

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Background: CYP2C9 is one of the most important phase I drug-metabolizing enzymes in liver. The objective of this work was to investigate the effects of apigenin on the metabolism of losartan and human CYP2C9 and rat CYP2C11 activity in vitro. Methods: Different concentrations of apigenin were added to a 100 mmol/l Tris-HCl reaction mixture containing 2 pmol/ml recombinant human CYP2C9.1, 0.25 mg/ml human liver microsomes or 0.5 mg/ml rat liver microsomes to determine the half maximal inhibition or a half-maximal inhibitory concentration (IC50) on the metabolism of losartan. In addition, diclofenac used as CYP2C9 substrate was performed to determine the effects of apigenin on CYP2C9. Results: The results showed that apigenin has the inhibitory effect on the metabolism of losartan in vitro, the IC50 was 7.61, 4.10 and 11.07 μmol/l on recombinant CYP2C9 microsomes, human liver microsomes and rat liver microsomes, respectively. Meanwhile, apigenin's mode of action on human CYP2C9 activity was competitive for the substrate diclofenac. In contrast to its potent inhibition of CYP2C9 in humans (9.51 μmol/l), apigenin had lesser effects on CYP2C11 in rat (IC50 = 15.51 μmol/l). Conclusion: The observations imply that apigenin has the inhibitory effect on the metabolism of losartan and CYP2C9 activity in vitro. More attention should be paid as to when losartan should be administrated combined with apigenin.

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“…This result is consistent with our previous reports on imatinib, which is catalyzed mainly by CYP3A4 [20,21,22]; co-administration with apigenin would result in higher concentrations of imatinib in the short term. The result significantly increased the AUC and reduced the CL after administering imatinib and apigenin in rats at a single dose [11]. CYP enzymes play an important role in the Phase I oxidation metabolism of a wide range of xenobiotics, and inhibition of CYP isoforms might influence the elimination of drugs and induce serious adverse drug response.…”

Section: Discussionmentioning

confidence: 99%

“…A similar result has been demonstrated by a previous research conducted in our laboratory. The influence of high-dose (252 mg/kg) short-time apigenin group in imatinib was less than that of low-dose (165 mg/kg) apigenin group, which indicated that the effect was not dose dependent [11]. …”

Section: Discussionmentioning

confidence: 99%

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Inhibitory Effect of Apigenin on Pharmacokinetics of Venlafaxine in vivo and in vitro

Zhan

Liang²,

Gu³

et al. 2015

Pharmacology

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Objective: This study was conducted to investigate the effects of orally administered apigenin on the pharmacokinetics of venlafaxine (VEN) in rats and on the metabolism of VEN in human and rat liver microsomes in vitro. Methods: Ten healthy male SD rats were randomly divided into 2 groups: A group (control group), B group (a single dose of 250 mg/kg apigenin). A single dose of 20 mg/kg VEN was administered orally 30 min after administration of apigenin (250 mg/kg). VEN plasma levels were measured by HPLC with fluorescence detection, and pharmacokinetic parameters were calculated by DAS 3.0 software. Results: The single dose of 250 mg/kg apigenin significantly increased the AUC_0-t of VEN by 40.9% (p < 0.05) and obviously increased the peak plasma concentration (C_max) of VEN (p < 0.05). Furthermore, apigenin showed inhibitory effect on human and rat microsomes and the IC₅₀ of apigenin was 58.37 and 25.73 μmol/l, respectively. Conclusions: Our results indicated that an intake of apigenin could increase VEN plasma levels and some of its pharmacokinetic parameters (AUC, T_max). Thus, more attention should be paid when VEN was administrated combined with apigenin.

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The Effect of Apigenin on Pharmacokinetics of Imatinib and Its Metabolite N-Desmethyl Imatinib in Rats

Cited by 13 publications

References 24 publications

Inhibitory effect of silybin on pharmacokinetics of imatinib in vivo and in vitro

Inhibitory effect of silybin on pharmacokinetics of imatinib in vivo and in vitro

Inhibitory Effect of Apigenin on Losartan Metabolism and CYP2C9 Activity in vitro

Inhibitory Effect of Apigenin on Pharmacokinetics of Venlafaxine in vivo and in vitro

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