ArticleDrug metabolism and disposition: the biological fate of chemicals2019
In Vitro-In Vivo Inaccuracy: The CYP3A4 Anomaly.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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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.
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Who cites it
9 citing papers in PubMed, 16 citations in OpenAlex.
- Prediction of a clinically effective dose of THY1773, a novel VBiopharmaceutics & drug disposition · 2021Trial
- Interaction of Cytochrome P450 3A4 with Fatty Acid Binding Protein 1 and Relevance to Drug Metabolism.Journal of medicinal chemistry · 2026Article
- A mismatch in enzyme-redox partnerships underlies divergent cytochrome P450 activities between human hepatocytes and microsomes.Communications biology · 2025Article
- Anti-Cryptosporidium efficacy of BKI-1708, an inhibitor of Cryptosporidium calcium-dependent protein kinase 1.PLoS neglected tropical diseases · 2025Article
- Albumin-conjugation enables improved tumor targeting of aptamers via SPECT imaging.Molecular therapy. Nucleic acids · 2025Article
- Mechanistic Static Model based Prediction of Transporter Substrate Drug-Drug Interactions Utilizing Atorvastatin and Rifampicin.Pharmaceutical research · 2023Article
- Analyzing the metabolic fate of oral administration drugs: A review and state-of-the-art roadmap.Frontiers in pharmacology · 2022Review
- Successful and Unsuccessful Prediction of Human Hepatic Clearance for Lead Optimization.Journal of medicinal chemistry · 2021Review
- Investigating the Theoretical Basis for In Vitro-In Vivo Extrapolation (IVIVE) in Predicting Drug Metabolic Clearance and Proposing Future Experimental Pathways.The AAPS journal · 2020Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
When predicting hepatic clearance using in vitro to in vivo extrapolation (IVIVE), microsomes or hepatocytes are commonly used. Here, we examine intrinsic clearance values and IVIVE results in human hepatocytes and microsomes for compounds metabolized by a variety of enzymes. The great majority of CYP3A4 substrates examined had higher intrinsic clearance values in microsomes compared with hepatocytes, whereas the values were more similar between the two incubations for substrates of other enzymes. We hypothesize that this may be due to interplay between CYP3A4 and the efflux transporter P-glycoprotein, as they have been shown to exhibit coordinated regulation. When examining the prediction accuracy for substrates of other enzymes between microsomes and hepatocytes, average fold errors as well as overall error were similar, demonstrating once again that IVIVE methods are not adequately defined and understood. SIGNIFICANCE STATEMENT: For CYP3A4 substrates, microsomes give markedly higher predictive in vitro to in vivo extrapolation than for other metabolic enzymes, which is not found for hepatocytes. We hypothesize that this could be a result of CYP3A4-P-glycoprotein interplay or coordinated regulation in hepatocytes that would not be observed in microsomes.
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Registered trials
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.