Metabolism of two new antiepileptic drugs and their principal metabolites S(+)- and R(-)-10,11-dihydro-10-hydroxy carbamazepine

Epilepsy Research
D HainzlP Soares-da-Silva

Abstract

BIA 2-093 and BIA 2-059 are two stereoisomers under development as new antiepileptic drugs. They act as prodrugs for the corresponding hydroxy derivatives (S(+)- or R(-)-10,11-dihydro-10-hydroxy carbamazepine, respectively) which are known to be the active metabolites of the antiepileptic drug oxcarbazepine (OXC). The purpose of this study was to define the metabolic pathway especially in terms of stereoselectivity, and to estimate the possibility of racemization in humans. For in vivo studies, the rat, mouse and rabbit were chosen as models in order to cover a broad spectrum of metabolic activity. In addition, incubations with liver microsomes from these three species plus dog and monkey were compared to results obtained with human liver microsomes. It was found that both drugs were almost instantly hydrolysed to the corresponding 10-hydroxy compounds in mice, rats and rabbits. Mice and rabbits were not able to oxidize the 10-hydroxy compounds to OXC in significant amounts. In the rat, BIA 2-093 also gave origin to OXC, whereas BIA 2-059 resulted in the formation of OXC and the trans-diol metabolite in equal amounts. It could be shown that the rat is able to reduce the formed OXC in liver to S(+)-10-hydroxy metabolite, resulti...Continue Reading

References

Jul 1, 1987·Journal of Neurology, Neurosurgery, and Psychiatry·J W Sander, S D Shorvon
Nov 1, 1987·Epilepsia·M A HoutkooperJ A Hulsman
Apr 1, 1988·The Journal of Pediatrics·L B Holmes
Aug 1, 1986·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·H SchützT Winkler
Jan 1, 1995·Pharmacology & Therapeutics·B Rogvi-Hansen, L Gram
Nov 1, 1996·British Journal of Clinical Pharmacology·E Perucca

❮ Previous
Next ❯

Citations

Nov 6, 2010·Der Nervenarzt·B J SteinhoffA S Wendling
May 23, 2012·Epilepsia·Meir Bialer, Patricio Soares-da-Silva
Jan 25, 2011·CNS Drugs·Linda J Stephen, Martin J Brodie
Nov 1, 2011·Drugs·Cinzia Fattore, Emilio Perucca
Nov 15, 2013·Epilepsy Research·Alberto VerrottiGaetano Zaccara
Mar 6, 2015·Expert Opinion on Drug Metabolism & Toxicology·Monika BanachStanisław J Czuczwar
May 30, 2008·Journal of Clinical Pharmacology·Luis AlmeidaPatrício Soares-da-Silva
Jun 26, 2010·Biopharmaceutics & Drug Disposition·Ana FortunaPatrício Soares-da-Silva
Jun 4, 2015·Pharmacology Research & Perspectives·Patrício Soares-da-SilvaLyndon C Wright
Jan 6, 2010·Acta Neurologica Scandinavica·L AlmeidaP Soares-da-Silva
Nov 1, 2013·Drug Metabolism Reviews·Petra Malátková, Vladimír Wsól
Aug 20, 2008·Fundamental & Clinical Pharmacology·Gilberto AlvesPatrício Soares-da-Silva
Jul 27, 2014·Chemico-biological Interactions·Petra MalátkováVladimír Wsól
May 31, 2006·Expert Opinion on Investigational Drugs·Meir Bialer
Mar 22, 2016·Expert Opinion on Pharmacotherapy·Jaime GierboliniSelim R Benbadis
Oct 25, 2012·Epilepsy & Behavior : E&B·Piero Perucca, Marco Mula
Feb 27, 2016·Acta Neurologica Scandinavica·M HoltkampE Kockelmann
Sep 14, 2010·Journal of Pharmaceutical and Biomedical Analysis·Mahesh Kumar Mone, K B Chandrasekhar
Feb 25, 2009·Expert Opinion on Investigational Drugs·Tiago Mestre, Joaquim Ferreira
Nov 10, 2010·Cephalalgia : an International Journal of Headache·Ulrike HoffmannCenk Ayata
Jul 3, 2015·Therapeutic Advances in Neurological Disorders·Rodrigo Rocamora
Sep 30, 2016·Scientific Reports·Fernanda de Lima MoreiraAnderson R M de Oliveira
Jan 1, 2011·Journal of Central Nervous System Disease·Rajinder P Singh, Jorge J Asconapé

❮ 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.