Assessments of CYP-inhibition-based drug-drug interaction between vonoprazan and poziotinib in vitro and in vivo

Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown. To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan. In vitro experiments were performed with rat liver microsomes (RLMs) and the contents...

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Published inPharmaceutical Biology Vol. 61; no. 1; pp. 356 - 361
Main Authors Zhou, Shan, Zhao, Fang-Ling, Wang, Shuang-Hu, Wang, Yi-Ran, Hong, Yun, Zhou, Quan, Geng, Pei-Wu, Luo, Qing-Feng, Cai, Jian-Ping, Dai, Da-Peng
Format Journal Article
LanguageEnglish
Published England Taylor & Francis 31.12.2023
Informa UK Limited
Taylor & Francis Ltd
Taylor & Francis Group
Subjects
Animals
Biological Sciences
blood
Chromatography, Liquid
computer software
CYP3A4
drug inhibition
Drug interaction
Drug Interactions
liver microsomes
Metabolism
Metabolites
Microsomes
Microsomes, Liver - metabolism
Pharmacokinetics
Rats
Research Article
RM1-950
Statistical analysis
statistical models
tail
Tandem Mass Spectrometry
Therapeutics. Pharmacology
UPLC-MS/MS
pharmacokinetics
UPLC-MS/MS
drug inhibition
CYP3A4
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Abstract Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown. To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan. In vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses. In vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC 50  = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant K i was 0.574 μM and the binding constant αK i was 2.77 μM. In vivo experiments revealed that the AUC (0- T ) (15.05 vs. 90.95 μg/mL·h) and AUC (0-∞) (15.05 vs. 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT (0-∞) of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib. Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.
AbstractList AbstractContext Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown.Objective To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan.Materials and methods In vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses.Results In vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC50 = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant Ki was 0.574 μM and the binding constant αKi was 2.77 μM. In vivo experiments revealed that the AUC(0-T) (15.05 vs. 90.95 μg/mL·h) and AUC(0-∞) (15.05 vs. 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT(0-∞) of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib.Conclusions Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.
Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown. To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan. experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses. experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC  = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant K was 0.574 μM and the binding constant αK was 2.77 μM. experiments revealed that the AUC (15.05 90.95 μg/mL·h) and AUC (15.05 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib. Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.
ContextPoziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown.ObjectiveTo study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan.Materials and methodsIn vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses.ResultsIn vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC50 = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant Ki was 0.574 μM and the binding constant αKi was 2.77 μM. In vivo experiments revealed that the AUC(0-T) (15.05 vs. 90.95 μg/mL·h) and AUC(0-∞) (15.05 vs. 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT(0-∞) of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib.ConclusionsPoziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.
Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown.CONTEXTPoziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown.To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan.OBJECTIVETo study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan.In vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses.MATERIALS AND METHODSIn vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses.In vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC50 = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant Ki was 0.574 μM and the binding constant αKi was 2.77 μM. In vivo experiments revealed that the AUC(0-T) (15.05 vs. 90.95 μg/mL·h) and AUC(0-∞) (15.05 vs. 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT(0-∞) of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib.RESULTSIn vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC50 = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant Ki was 0.574 μM and the binding constant αKi was 2.77 μM. In vivo experiments revealed that the AUC(0-T) (15.05 vs. 90.95 μg/mL·h) and AUC(0-∞) (15.05 vs. 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT(0-∞) of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib.Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.CONCLUSIONSPoziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.
Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown. To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan. In vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses. In vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC 50  = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant K i was 0.574 μM and the binding constant αK i was 2.77 μM. In vivo experiments revealed that the AUC (0- T ) (15.05 vs. 90.95 μg/mL·h) and AUC (0-∞) (15.05 vs. 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT (0-∞) of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib. Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.
Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown. To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan. In vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses. In vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC₅₀ = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant Kᵢ was 0.574 μM and the binding constant αKᵢ was 2.77 μM. In vivo experiments revealed that the AUC₍₀₋ T ₎ (15.05 vs. 90.95 μg/mL·h) and AUC₍₀₋∞₎ (15.05 vs. 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT₍₀₋∞₎ of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib. Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.
Author Hong, Yun
Zhou, Quan
Zhao, Fang-Ling
Zhou, Shan
Dai, Da-Peng
Cai, Jian-Ping
Luo, Qing-Feng
Geng, Pei-Wu
Wang, Yi-Ran
Wang, Shuang-Hu
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  fullname: Zhao, Fang-Ling
  organization: Peking University Fifth School of Clinical Medicine
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  fullname: Wang, Shuang-Hu
  organization: Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui
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  givenname: Yi-Ran
  surname: Wang
  fullname: Wang, Yi-Ran
  organization: Department of Gastroenterology, Beijing Hospital, National Center of Gerontology
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  givenname: Yun
  surname: Hong
  fullname: Hong, Yun
  organization: Department of Gastroenterology, Beijing Hospital, National Center of Gerontology
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  fullname: Zhou, Quan
  organization: Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui
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  givenname: Pei-Wu
  surname: Geng
  fullname: Geng, Pei-Wu
  organization: Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui
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  givenname: Qing-Feng
  surname: Luo
  fullname: Luo, Qing-Feng
  organization: Institute of Geriatric Medicine, Chinese Academy of Medical Sciences
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  surname: Cai
  fullname: Cai, Jian-Ping
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Issue 1
Keywords pharmacokinetics
UPLC-MS/MS
drug inhibition
CYP3A4
Language English
License open-access: http://creativecommons.org/licenses/by/4.0/: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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These authors contributed equally to this work.
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Snippet Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown. To study the interaction...
ContextPoziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown.ObjectiveTo study the...
Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown.CONTEXTPoziotinib and...
Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown. To study the interaction...
AbstractContext Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown.Objective To...
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StartPage 356
SubjectTerms Animals
Biological Sciences
blood
Chromatography, Liquid
computer software
CYP3A4
drug inhibition
Drug interaction
Drug Interactions
liver microsomes
Metabolism
Metabolites
Microsomes
Microsomes, Liver - metabolism
Pharmacokinetics
Rats
Research Article
RM1-950
Statistical analysis
statistical models
tail
Tandem Mass Spectrometry
Therapeutics. Pharmacology
UPLC-MS/MS
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Title Assessments of CYP-inhibition-based drug-drug interaction between vonoprazan and poziotinib in vitro and in vivo
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