Cytochrome P450 3A (CYP3A), the most important class of drug-metabolizing enzymes, participates in the metabolism of half of clinically used drugs. The CYP3A index reactions of dogs, one of the most widely used preclinical nonrodent species, are still poorly understood. This work evaluated the activity and selectivity of 10 CYP3A index reactions, including midazolam (MDZ) 1'- and 4-hydroxylation, alprazolam (APZ) and triazolam (TRZ) - and 4-hydroxylation, testosterone (T) 6-hydroxylation, lithocholate (LCA) 6-hydroxylation, deoxycholate (DCA) 1- and 5-hydroxylation, with quantitative reaction phenotyping and kinetic analysis in human and canine recombinant CYP enzymes (rCYPs). In human studies, all reactions are reconfirmed as mixed index reactions of CYP3A with minor contributions from non-CYP3A isoforms. In canine studies, all reactions are also primarily catalyzed by CYP3A12 with lower contributions from CYP3A26. However, the canine CYP2B11 appreciably contributes to the hydroxylation of benzodiazepines except for APZ 4-hydroxylation. The canine CYP3A isoforms have lower activity than human isoforms toward T 6-hydroxylation and LCA 6-hydroxylation and both substrates undergo non-CYP3A catalyzed side reactions. DCA 1- and 5-hydroxylation are validated as the CYP3A index reactions in both humans and dogs with limited non-CYP3A contributions and side reactions. In conclusion, this work provides a comprehensive overview for the selectivity and activity of in vitro CYP3A index reactions in humans and dogs. The validated CYP3A index reactions between humans and dogs may benefit future practices in drug metabolism and drug interaction studies. SIGNIFICANCE STATEMENT: Dogs are one of the most important nonrodent animals with limited studies of cytochrome P450 enzymes than humans. This work provides the most comprehensive quantitative data to date for the selectivity and activity of CYP3A index reactions in humans and dogs. The canine CYP2B11 was found to appreciably contribute to hydroxylation of midazolam, alprazolam and triazolam, the well-known probes for human CYP3A. Deoxycholate 1- and 5-hydroxylation are validated as the CYP3A index reactions in both humans and dogs.
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http://dx.doi.org/10.1124/dmd.122.000864 | DOI Listing |
Expert Opin Drug Metab Toxicol
November 2024
Research and Development Department, Promega Corporation, Madison, WI, USA.
Background: Adverse drug-drug interactions (DDI) may occur when one drug accelerates or slows a second drug's metabolism by, respectively, inducing or inhibiting a cytochrome P450 (CYP) that metabolizes that second drug. We developed an method employing urinalysis to complement CYP induction and inhibition measurements widely used to predict DDIs.
Research Design And Methods: Focusing on Cyp3a enzymes, the major mammalian drug metabolizers, we applied luciferin-IPA, a selective Cyp3a probe substrate to mice after Cyp3a inducers and inhibitor treatments.
Clin Lymphoma Myeloma Leuk
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Department of Pharmacy, Paris Public Hospital at Home (HAD AP-HP), University Hospitals of Paris, Paris, France.
J Affect Disord
February 2025
Department of Clinical Pharmacy, The First Hospital of Hebei Medical University, Shijiazhuang, China; The Technology Innovation Center for Artificial Intelligence in Clinical Pharmacy of Hebei Province, The First Hospital of Hebei Medical University, Shijiazhuang, China. Electronic address:
Background: The involvement of cytochrome P450 3A5 (CYP3A5) in the metabolism of quetiapine has been proposed, though conclusive evidence is lacking. This study aimed to quantitatively assess the impact of CYP3A5 genetic variability on quetiapine exposure in a Chinese patient population.
Methods: Patient data were retrospectively collected from the database of the Mental Health Centre at the First Hospital of Hebei Medical University, covering the period from September 1, 2019, to July 1, 2023.
J Proteome Res
November 2024
Institute for Systems Biology, Seattle, Washington 98109, United States.
Drug Des Devel Ther
October 2024
Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
Background: Anlotinib was approved as a third line therapy for advanced non-small cell lung cancer in China. However, the impact of concurrent administration of various clinical drugs on the drug-drug interaction (DDI) potential of anlotinib remains undetermined. As such, this study aims to evaluate the DDI of anlotinib as a victim by establishing a physiologically based pharmacokinetic (PBPK) model.
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