Evidence map›Paper›PMID 40721555›Full record

ArticleThe AAPS journal2025

Double-humanized Rats for CYP3A and PXR as an Improved Model for Analyzing Drug-drug Interactions Mediated by CYP3A4.

Kaoru Kobayashi, Genki Minegishi, Kanako Kazuki, Satoshi Abe, Miyuki Sato, Atsushi Miyajima, Masumi Hirabayashi, Tetsushi Sakuma, Takashi Yamamoto, Yasuhiro Kazuki

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Article in The AAPS journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Kaoru KobayashiDepartment of Biopharmaceutics, Graduate School of Clinical Pharmacy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan. kaoruk@my-pharm.ac.jp.ORCID 0000-0002-8105-6377
Genki MinegishiDepartment of Biopharmaceutics, Graduate School of Clinical Pharmacy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.ORCID 0009-0009-2421-0532
Kanako KazukiChromosome Engineering Research Center (CERC), Tottori University, Tottori, Japan.ORCID 0009-0009-4827-2391
Satoshi AbeChromosome Engineering Research Center (CERC), Tottori University, Tottori, Japan.ORCID 0000-0003-1153-0720
Miyuki SatoDepartment of Biopharmaceutics, Graduate School of Clinical Pharmacy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.ORCID 0009-0008-5055-9626
Atsushi MiyajimaDepartment of Biopharmaceutics, Graduate School of Clinical Pharmacy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.ORCID 0009-0009-1514-8773
Masumi HirabayashiCenter for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Japan.ORCID 0000-0002-1059-5883
Tetsushi SakumaGraduate School of Agriculture, Kyoto University, Kyoto, Japan.ORCID 0000-0003-0396-1563
Takashi YamamotoDivision of Integrated Sciences for Life, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan.ORCID 0000-0002-6516-2903
Yasuhiro KazukiChromosome Engineering Research Center (CERC), Tottori University, Tottori, Japan. kazuki@tottori-u.ac.jp.ORCID 0000-0003-4818-4710

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The human cytochrome P450 3A4 (CYP3A4) enzyme, which is expressed in the liver and the intestines, catalyzes the metabolism of numerous drugs. The induction of CYP3A4 by the pregnane X receptor (PXR) represents a significant problem in pharmacotherapy. Since the metabolic properties of CYP3A substrates and the recognition of PXR ligands differ between humans and rats, there are limitations to reproducing human CYP3A4 induction in rat studies. Here, we developed a double-humanized rat model for CYP3A and PXR to mimic drug-drug interactions in humans using a rat model. The model was created using a combination of mammalian artificial chromosome-based chromosome engineering, bacterial artificial chromosome-based transgenic technology, and genome editing. The resulting double-humanized rat model for CYP3A and PXR (huCYP3A-PXR rat) was treated with rifampicin, a human PXR ligand. This treatment increased CYP3A4 mRNA expression in the liver and intestine and enhanced the hydroxylation activities of triazolam, a CYP3A4 substrate. Pretreatment with rifampicin resulted in a reduction of triazolam plasma concentrations and an increase in its metabolites after oral administration. Furthermore, ketoconazole, a CYP3A4 inhibitor, led to an increase in triazolam plasma concentrations and a decrease in its metabolites in huCYP3A-PXR rats regardless of pretreatment with rifampicin. These results suggest that huCYP3A-PXR rats could predict human CYP3A4 induction and inhibition in vivo. This innovative model, in which PXR and CYP3A are humanized, is expected to be a valuable tool for studying drug-drug interactions, including a combination of inducers and inhibitors, and to be integrated into the preclinical drug-development pipeline in future.

Indexed as

Cytochrome P-450 CYP3APregnane X ReceptorAnimalsCytochrome P-450 CYP3A InducersCytochrome P-450 CYP3A InhibitorsDrug InteractionsHumansKetoconazoleLiverMaleModels, AnimalRatsRats, TransgenicRifampinTriazolamCYP3A4 protein, humanCytochrome P-450 CYP3ACytochrome P-450 CYP3A InducersCytochrome P-450 CYP3A InhibitorsKetoconazolePregnane X ReceptorRifampinTriazolamChromosomesCYP3ADrug interactionGene editingPregnane X receptor

Identifiers

PMID40721555

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.