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.
Breast cancer resistance protein (BCRP/ABCG2) is a novel member of ATP-binding cassette transporters, which induce multidrug resistance in cancer cells. We found that a high level of BCRP expression in CD4 ϩ T cells conferred cellular resistance to human immunodeficiency virus type-1 (HIV-1) nucleoside reverse transcriptase inhibitors. The cell line MT-4/DOX 500 was established through the long-term culture of MT-4 cells in the presence of doxorubicin (DOX) and had reduced sensitivity to not only DOX but also zidovudine (AZT). MT-4/DOX 500 cells showed reduced intracellular accumulation and retention of DOX and increased ATP-dependent rhodamine 123 efflux. The cells were also resistant to several anticancer agents such as mitoxantrone, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, and 7-ethyl-10-hydroxycamptothecin. AZT was 7.5-fold less inhibitory to HIV-1 replication in MT-4/DOX 500 cells than in MT-4 cells. Furthermore, the anti-HIV-1 activity of lamivudine was severely impaired in MT-4/DOX 500 cells. In contrast, the antiviral activity of non-nucleoside reverse transcriptase inhibitors and protease inhibitors was not affected in the cells. MT-4/DOX 500 cells expressed glycosylated BCRP but not P-glycoprotein (ABCB1), multidrug resistance protein 1, 2, or 4 (ABCC1, -2, or -4), or lung resistance-related protein. In addition, the BCRP-specific inhibitor fumitremorgin C completely abolished the resistance of MT-4/DOX 500 cells to AZT as well as to DOX. An analysis for intracellular metabolism of AZT suggests that the resistance is attributed to the increase of ATP-dependent efflux of its metabolites, presumably AZT 5Ј-monophosphate, in MT-4/DOX 500 cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.