Autoinduction of MKC-963 [(R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine] metabolism in healthy volunteers and its retrospective evaluation using primary human hepatocytes and cDNA-expressed enzymes

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Toshiyuki ShimizuK Chiba

Abstract

MKC-963, (R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine, a potent inhibitor of platelet aggregation, was synthesized and used in clinical trials in the 1990s. In the process of clinical study, it was found that urinary excretion ratios for 6beta-hydroxycortisol and free cortisol increased significantly in parallel with decreases in the plasma concentrations of MKC-963 after repeated oral administration of the compound to healthy volunteers. These findings suggested that MKC-963 caused autoinduction (defined as the ability of a drug to induce enzymes that enhance its own metabolism, resulting in dispositional tolerance) in humans, and clinical studies using the compound were stopped. This experience prompted us to reevaluate the effects of this compound on CYP3A4 using primary human hepatocytes and cDNA-expressed human cytochrome P450 (P450) enzymes to determine whether the autoinduction of MKC-963 metabolism in humans could have been predicted if these in vitro systems had been used for the evaluation of MKC-963 in the preclinical study. The results of in vitro study showed that MKC-963 increased CYP3A4 mRNA expression level and activity of testosterone 6beta-hydroxylation to extents similar to those observed with rifampici...Continue Reading

References

Nov 1, 1992·The Journal of Clinical Investigation·J C KolarsP B Watkins
Jan 1, 1990·Cancer Chemotherapy and Pharmacology·Y MitsuhashiT Kobayashi
Jan 1, 1989·European Journal of Clinical Pharmacology·E E OhnhausB K Park
Oct 1, 1987·The Journal of Clinical Investigation·P B WatkinsP S Guzelian
Dec 15, 1995·Toxicology·A P LiA Rasmussen
Jan 1, 1997·Pharmacology & Therapeutics·T IwatsuboY Sugiyama
Jun 2, 1998·The Annals of Pharmacotherapy·G D Anderson
May 1, 1999·Clinical Pharmacology and Therapeutics·K VillikkaP J Neuvonen
Oct 24, 2000·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·D A Smith
Nov 12, 2002·Clinical Pharmacology and Therapeutics·Wibool RidtitidMethi Sunbhanich
Mar 19, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jasminder SahiMichael W Sinz
Jul 10, 2003·British Journal of Clinical Pharmacology·Thomayant PrueksaritanontNathan Yu
Jul 1, 1993·Toxicology in Vitro : an International Journal Published in Association with BIBRA·M T DonatoJ V Castell

❮ Previous
Next ❯

Citations

Sep 24, 2013·Biochemical Pharmacology·Jianghong Fan, Inés A M de Lannoy
May 9, 2007·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Y D GaoR T Mosley
Nov 6, 2012·Expert Review of Clinical Pharmacology·Janne Hukkanen

❮ 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.

© 2021 Meta ULC. All rights reserved