Cytochrome P450 3A selectively affects the pharmacokinetic interaction between erlotinib and docetaxel in rats

Qin, Xuan; Lu, Jian; Wang, Peili; Xu, Peipei; Liu, Mingyao; Wang, Xin

doi:10.1016/j.bcp.2017.07.013

Cited by 17 publications

(11 citation statements)

References 36 publications

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“…Furthermore, DMPK animal models will promote the study of DMPK mechanisms and strengthen the relationship between drug metabolism and pharmacology/toxicology. For example, the potentials and mechanisms of DDI between erlotinib and docetaxel was studies by using Cyp3a1/2 KO rats 320 . Docetaxel significantly increased the maximum concentration and systemic exposure of erlotinib in wild type (WT) rats, but the DDI was significantly attenuated in Cyp3a1/2 KO rats, suggesting that the CYP3A plays the perpetrating role of docetaxel on erlotinib.…”

Section: Novel Animal Models For Dmpk Studiesmentioning

confidence: 99%

Current trends in drug metabolism and pharmacokinetics

Meng

Yang

et al. 2019

Acta Pharmaceutica Sinica B

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213

124

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Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug–drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice.

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Section: Novel Animal Models For Dmpk Studiesmentioning

confidence: 99%

Current trends in drug metabolism and pharmacokinetics

Meng

Yang

et al. 2019

Acta Pharmaceutica Sinica B

Self Cite

213

124

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“…The CYP1A2 KO rat model was generated by CRISPR/Cas9 technology, which was modified from our previous research (Wang et al, 2016;Lu et al, 2017). The CYP1A2 gene sequence of Rattus norvegicus (Norwegian rat) was obtained from NCBI (https://www.ncbi.nlm.nih.gov/pmc/).…”

Section: Generation Of Cyp1a2 Ko Rat Modelmentioning

confidence: 99%

“…The construction of gene editing rats by CRISPR/Cas9 technology has made great progress in drug metabolism and pharmacokinetics (Lu et al, 2021). For example, we have successfully constructed CYP2E1 (-/-) (Wang et al, 2016), CYP3A1/2 (-/-) (Lu et al, 2017), CYP2J3/10 (-/-) (Lu et al, 2020a), Mdr1a/b (-/-) (Liang et al, 2019), and Slco1b2 (-/-) (Ma et al, 2020) rat models through CRISPR/Cas9, and applied them to the exploration of pharmacokinetics and drug-drug interactions Qin et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Sun

Zhang

et al. 2021

Drug Metab Dispos

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Cytochrome P450 1A2 (CYP1A2) as one of the most important CYP isoforms is involved in the biotransformation of many important endogenous and exogenous substances. CYP1A2 also plays an important role in the development of many diseases because it is involved in the biotransformation of precancerous substances and poisons. Although the generation of Cyp1a2 knockout (KO) mouse model has been reported, there are still no relevant rat models for the study of CYP1A2-mediated pharmacokinetics and diseases. In this report, CYP1A2 KO rat model was established successfully by CRISPR/Cas9 without any detectable off-target effect. Compared with wild-type rats, this model showed a loss of CYP1A2 protein expression in the liver. The results of pharmacokinetics in vivo and incubation in vitro of specific substrates of CYP1A2 confirmed the lack of function of CYP1A2 in KO rats. In further studies of potential compensatory effects, we found that CYP1A1 was significantly up-regulated, and CYP2E1, CYP3A2 and LXRβ were down-regulated in KO rats. In addition, CYP1A2 KO rats exhibited a significant increase in serum cholesterol and free testosterone, accompanied by mild liver damage and lipid deposition, suggesting that CYP1A2 deficiency affects lipid metabolism and liver function to a certain extent. In summary, we successfully constructed the CYP1A2 KO rat model, which provides a useful tool for studying the metabolic function and physiological function of CYP1A2.

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“…Although the molecular mechanisms of HDIs are diverse, most cases of the clinically relevant HDIs are related with pharmacokinetic alterations (Qin et al, 2017;Sun et al, 2017;Dunkoksung et al, 2019;Ge, 2019), in which co-administrated herbal products alter the function or expression of drug metabolizing enzymes or transporters that are responsible for the elimination of the therapeutic agents. Unfortunately, to date, the interactions between the major constituents in Ophiopogonis Radix and drug-metabolizing enzymes in humans are rarely investigated.…”

Section: Discussionmentioning

confidence: 99%

Reversible and Irreversible Inhibition of Cytochrome P450 Enzymes by Methylophiopogonanone A

Mao

Zhang

et al. 2021

Drug Metab Dispos

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Methylophiopogonanone A (MOA), an abundant homoisoflavonoid bearing a methylenedioxyphenyl (MDP) moiety, is one of the major consitituents in the Chinese herb Ophiopogon japonicas. This work aims to assess the inhibitory potentials of MOA against cytochrome P450 enzymes, as well as to decipher the molecular mechanisms for CYP inhibition by MOA. The results showed that MOA concentration-dependently inhibited CYPs1A, 2C8, 2C9, 2C19 and 3A in human liver microsomes (HLMs) in a reversible way, with IC 50 values varying from 1.06 μM to 3.43 μM. By contrast, MOA time-, concentrationand NADPH-dependently inhibited CYP2D6 and CYP2E1, along with K I and k inact values of 207 µM and 0.07 min -1 for CYP2D6, as well as 20.9 µM and 0.03 min -1 for CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by GSH in a HLM incubation system, while CYPs2D6, 1A2 and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-qunione intermediate.Additionally, the potential risks of herb-drug interactions triggered by MOA or MOA-related products were also predicted. Collectively, our findings verify that MOA is a reversible inhibitor of CYPs1A, 2C8, 2C9, 2C19 and 3A but acts as an inactivator of CYP2D6 and CYP2E1.

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Cytochrome P450 3A selectively affects the pharmacokinetic interaction between erlotinib and docetaxel in rats

Cited by 17 publications

References 36 publications

Current trends in drug metabolism and pharmacokinetics

Current trends in drug metabolism and pharmacokinetics

Characterization of a Novel CYP1A2 Knockout Rat Model Constructed by CRISPR/Cas9

Reversible and Irreversible Inhibition of Cytochrome P450 Enzymes by Methylophiopogonanone A

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