PXD039271

PXD039271 is an original dataset announced via ProteomeXchange.

Title	Quantitative Characterization of Clinically Relevant Drug-Metabolizing Enzymes and Transporters in Rat Liver and Intestinal Segments for Applications in PBPK Modeling
Description	Rats are extensively used preclinical models for assessing drug pharmacokinetics (PK) and tissue distribution; however, a successful translation of the rat data requires information on the differences in drug metabolism and transport mechanisms between rats and humans. To partly fill this knowledge gap, we quantified clinically-relevant drug-metabolizing enzymes and transporters (DMET) in the liver and different intestinal segments of Sprague Dawley rats. The levels of DMET proteins in rats were quantified using global proteomics-based total protein approach (TPA) and targeted proteomics. The abundance of DMET proteins was largely comparable using quantitative global and targeted proteomics. Global proteomics-based TPA was able to detect and quantify a comprehensive list of 69 DMET proteins in the liver and 36 DMET proteins in the intestinal segments of SD rats without the need for peptide standards. Cytochrome P450 (Cyp) and UDP-glycosyltransferase (Ugt) enzymes were mainly detected in the liver with the abundance ranging from 8 to 6502, and 74 to 2557 pmol/g tissue. P-gp abundance was higher in the intestine (124.1 pmol/g) as compared to the liver (26.6 pmol/g) using the targeted analysis. Breast cancer resistance protein (Bcrp) was most abundant in the intestinal segments, whereas organic anion transporting polypeptide (Oatp) 1a1, 1a4, 1b2 and 2a1, and multidrug resistance protein (Mrp) 2 and 6 were predominantly detected in the liver. To demonstrate utility of these data, we modeled digoxin PK by integrating protein abundance of P-gp and Cyp3a2 into a physiologically-based PK (PBPK) model constructed using PK-Sim software. The model was able to reliably predict the systemic as well as tissue concentrations of digoxin in rats. These findings suggest that proteomics-informed PBPK models in preclinical species can allow mechanistic PK predictions in animal models including tissue drug concentrations.
HostingRepository	PRIDE
AnnounceDate	2025-02-05
AnnouncementXML	Submission_2025-02-05_12:13:34.614.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bhagwat Prasad
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF; Xevo TQ-XS

Revision	Datetime	Status	ChangeLog Entry
0	2023-01-05 02:15:10	ID requested
⏵ 1	2025-02-05 12:13:35	announced

Sharma S, Singh DK, Mettu VS, Yue G, Ahire D, Basit A, Heyward S, Prasad B, Quantitative Characterization of Clinically Relevant Drug-Metabolizing Enzymes and Transporters in Rat Liver and Intestinal Segments for Applications in PBPK Modeling. Mol Pharm, 20(3):1737-1749(2023) [pubmed]

10.1021/acs.molpharmaceut.2c00950;

submitter keyword: PBPK modeling,Quantitative proteomics, Drug metabolism, Total protein approach, Digoxin, Drug transport, Interspecies differences

Bhagwat Prasad
contact affiliation	College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
contact email	bhagwat.prasad@wsu.edu
lab head
Bhagwat Prasad
contact affiliation	Washington State University
contact email	bhagwat.prasad@wsu.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/02/PXD039271

PRIDE project URI

• PRIDE
  1. PXD039271
     1. Label: PRIDE project
     2. Name: Quantitative Characterization of Clinically Relevant Drug-Metabolizing Enzymes and Transporters in Rat Liver and Intestinal Segments for Applications in PBPK Modeling