Evaluation of in vitro absorption, distribution, metabolism, and excretion and assessment of drug-drug interaction of rucaparib, an orally potent poly(ADP-ribose) polymerase inhibitor

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Mingxiang LiaoJim Xiao

Abstract

1. The absorption, distribution, metabolism, elimination, and drug-drug interaction (DDI) potential of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was characterised in vitro.2. Rucaparib showed moderate cellular permeability, moderate human plasma protein binding (70.2%), and slow metabolism in human liver microsomes (HLMs). In HLMs, cytochrome P450 (CYP) 1A2 and CYP3A contributed to the metabolism of rucaparib to its major metabolite M324 with estimated fractions of metabolism catalysed by CYP (fm,CYP) of 0.27 and 0.64, respectively. Rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3As (IC50, 3.55, 12.9, 5.42, 41.6, and 17.2-22.9 µM [2 substrates], respectively), but not CYP2B6 or CYP2C8 (>190 µM). No time-dependent inhibition of any CYP was observed. In cultured human hepatocytes, rucaparib showed concentration-dependent induction of CYP1A2 mRNA and downregulation of CYP3A4 and CYP2B6 mRNA. In transfected cells expressing drug transporters, rucaparib was a substrate for P-gp and BCRP, but not for OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Rucaparib inhibited P-gp and BCRP (IC50, 169 and 55 µM, respectively) and slightly inhibited OATP1B1, OATP1B3, OAT1, and OAT3 (66%, 58%, 58%, and 42% inhibit...Continue Reading

References

Mar 17, 2007·Molecular Cancer Therapeutics·Huw D ThomasNicola J Curtin
Jan 2, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·K Herédi-SzabóP Krajcsi
Mar 9, 2011·Nature Medicine·Kornelia Polyak, Judy Garber
Oct 25, 2011·Journal of the American Society of Nephrology : JASN·Sushrut S WaikarJoseph V Bonventre
Feb 22, 2012·Nature Biotechnology·Elisabet WahlbergJohan Weigelt
Dec 21, 2013·Molecular Cancer Therapeutics·Junko MuraiYves Pommier
Mar 8, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Rebecca KristeleitRonnie Shapira-Frommer
Mar 23, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ravindranath Reddy GilibiliYurong Lai
May 16, 2018·Clinical Pharmacology and Therapeutics·Maciej J Zamek-GliszczynskiUNKNOWN International Transporter Consortium
May 26, 2018·Clinical Pharmacology in Drug Development·Geoffrey I ShapiroJim J Xiao
Aug 12, 2018·Pharmaceutics·Ravindranath Reddy GilibiliSagnik Chatterjee
Nov 19, 2018·Clinical Pharmacology and Therapeutics·Jill C ChappellJoseph V Bonventre
Apr 12, 2019·Acta Pharmaceutica Sinica. B·Xia LvLing Yang
Dec 4, 2019·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·Graziela Zibetti Dal MolinRobert L Coleman
Feb 23, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Wassim AbidaSimon Chowdhury

❮ Previous
Next ❯

Citations

Mar 9, 2021·Frontiers in Pharmacology·Shiwei ZhouYan Shu
Mar 31, 2021·Journal of Hematology & Oncology·Diego TeyssonneauGuilhem Roubaud
Apr 29, 2021·Cancer Chemotherapy and Pharmacology·Nikolay GrechkoJim Xiao
Apr 27, 2021·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Han LiYue Gao
Jul 31, 2021·British Journal of Clinical Pharmacology·Daranjit SandhuAlan M Jones
Aug 28, 2021·Progress in Lipid Research·Magdolna SzántóPeter Bai

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.