Abstract
Dihydroergocristine (DHEC) is a semi-synthetic drug mainly used for age-related cognitive impairment. In this study, its major metabolite 8-hydroxy-dihydroergocristine (8-OH-DHEC) was produced in incubates of a bovine liver preparation using dihydroergocristine mesylate (DHECM) as substrate. Purification was achieved by flash silica gel column and reverse phase liquid chromatographies, and identification was based on accurate molecular mass measurements, mass fragmentation spectra and NMR ( 1H/13C) chemical shifts. By using the substance produced in vitro, a fast, sensitive, specific and robust LC/MS/MS method for the simultaneous determination of DHEC and its major metabolite in human plasma was developed and validated. Bromocriptine was used as internal standard and limits of quantification for DHEC and 8-OH-DHEC were 10 pg/ml and 20 pg/ml, respectively. Pharmacokinetic parameters were investigated on 12 male healthy volunteers to whom a single dose of 18 mg DHECM was administered in tablets (Iskevert®). The peak of DHEC was 0.28 ± 0.22 μg/l, the tmax 0.46 ± 0.26 h, the AUClast 0.39 ± 0.41 µg/l.h and the terminal elimination half-life 3.50 ± 2.27 h. The peak of 8-OH-DHEC was 5.63 ± 3.34 µg/l, the tmax 1.04 ± 0.66 h, the AUClast 13.36 ± 5.82 μg/l.h and the terminal elimination half-life 3.90 ± 1.07 h. Dosing of 18 mg DHECM was well tolerated, causing no adverse events.
Keywords: Dihydroergocristine, 8'-Hydroxydihydroergocristine, Pharmacokinetics, LC/MS/MS
Current Drug Metabolism
Title: Pharmacokinetics of Dihydroergocristine and Its Major Metabolite 8- Hydroxy-Dihydroergocristine in Human Plasma
Volume: 6 Issue: 6
Author(s): Beatriz Bicalho, Giovanni C. Guzzo, Sergio Lilla, Hilton O. d. Santos, Gustavo D. Mendes, Giuseppe Caliendo, Elisa Perissutti, Anna Aiello, Paolo Luciano, Vicenzo Santagada, Alberto S. Pereira and > De Nucci
Affiliation:
Keywords: Dihydroergocristine, 8'-Hydroxydihydroergocristine, Pharmacokinetics, LC/MS/MS
Abstract: Dihydroergocristine (DHEC) is a semi-synthetic drug mainly used for age-related cognitive impairment. In this study, its major metabolite 8-hydroxy-dihydroergocristine (8-OH-DHEC) was produced in incubates of a bovine liver preparation using dihydroergocristine mesylate (DHECM) as substrate. Purification was achieved by flash silica gel column and reverse phase liquid chromatographies, and identification was based on accurate molecular mass measurements, mass fragmentation spectra and NMR ( 1H/13C) chemical shifts. By using the substance produced in vitro, a fast, sensitive, specific and robust LC/MS/MS method for the simultaneous determination of DHEC and its major metabolite in human plasma was developed and validated. Bromocriptine was used as internal standard and limits of quantification for DHEC and 8-OH-DHEC were 10 pg/ml and 20 pg/ml, respectively. Pharmacokinetic parameters were investigated on 12 male healthy volunteers to whom a single dose of 18 mg DHECM was administered in tablets (Iskevert®). The peak of DHEC was 0.28 ± 0.22 μg/l, the tmax 0.46 ± 0.26 h, the AUClast 0.39 ± 0.41 µg/l.h and the terminal elimination half-life 3.50 ± 2.27 h. The peak of 8-OH-DHEC was 5.63 ± 3.34 µg/l, the tmax 1.04 ± 0.66 h, the AUClast 13.36 ± 5.82 μg/l.h and the terminal elimination half-life 3.90 ± 1.07 h. Dosing of 18 mg DHECM was well tolerated, causing no adverse events.
Export Options
About this article
Cite this article as:
Bicalho Beatriz, Guzzo C. Giovanni, Lilla Sergio, Santos O. d. Hilton, Mendes D. Gustavo, Caliendo Giuseppe, Perissutti Elisa, Aiello Anna, Luciano Paolo, Santagada Vicenzo, Pereira S. Alberto and Nucci De >, Pharmacokinetics of Dihydroergocristine and Its Major Metabolite 8- Hydroxy-Dihydroergocristine in Human Plasma, Current Drug Metabolism 2005; 6 (6) . https://dx.doi.org/10.2174/138920005774832669
DOI https://dx.doi.org/10.2174/138920005774832669 |
Print ISSN 1389-2002 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5453 |
Call for Papers in Thematic Issues
Exploring oxidative stress and the anti-oxidant defense system in chronic diseases: therapeutic strategies and future perspective
Ageing is facilitated by oxidative stress (OS), which happens spontaneously. Several studies have demonstrated that OS over an extended period of time has a role in the emergence of several chronic illnesses. Diabetes, cancer, and heart disease are a few examples of these ailments. An imbalance between the body's antioxidants ...read more
Impact of brain tissue binding and plasma protein binding of drugs in DMPK
The impression of brain tissue binding (BTB) or plasma protein binding (PPB) in Drug Metabolism and Pharmacokinetics is critical to understanding the distribution, efficacy, and potential toxicity of drugs that target the central nervous system (CNS). BTB and high PPB influence the distribution of drugs in the body and their ...read more
Interaction between drugs and endocrine diseases
The introduction of highly active antiretroviral therapy accelerated studies and our understanding on the interaction between pharmacological therapies and endocrine diseases. Drugs can precipitate endocrine via different mechanisms, including direct alteration of hormone production and secretion, dysregulation of hormonal axis, effects on hormonal transport, receptor-binding, and cellular signalling. Common drug-induced ...read more
Metabolism-mediated xenobiotic toxicity
Considering the potent modulation of biotransformation enzyme expression and activities by various therapeutic drugs and environmental chemicals, and the commonly combined exposure of humans to both drugs and the ever increasing environmental pollutants simultaneously, knowledge about the combined toxic effects by modulating biotransformation enzymes, such as P450s, UDP- glucuronosyltransferases, and ...read more
Related Journals
![](/images/wayfinder.jpg)
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Development of Fluorinated Thienylchalcones as Monoamine Oxidase-B Inhibitors: Design, Synthesis, Biological Evaluation and Molecular Docking Studies
Letters in Organic Chemistry Cognitive Dysfunction in Major Depressive Disorder: A State-of-the-Art Clinical Review
CNS & Neurological Disorders - Drug Targets Machine Learning and Molecular Dynamics Based Insights into Mode of Actions of Insulin Degrading Enzyme Modulators
Combinatorial Chemistry & High Throughput Screening Development of Novel Genomic Blood Biomarkers for Neurodegenerative Diseases
CNS & Neurological Disorders - Drug Targets The Importance of Complying with Vaccination Protocols in Developed Countries: “Anti-Vax” Hysteria and the Spread of Severe Preventable Diseases
Current Medicinal Chemistry Overcoming Treatment Barriers in Adolescent Psychiatry
Adolescent Psychiatry Distinctive Effects of Aerobic and Resistance Exercise Modes on Neurocognitive and Biochemical Changes in Individuals with Mild Cognitive Impairment
Current Alzheimer Research Meet Our Editorial Board Member
Infectious Disorders - Drug Targets HGF-Antagonists: Structure, Activities, and Anti-cancer Approach
Current Signal Transduction Therapy Editorial (Hot Topic: Epidemiology & Risk Factors for Alzheimer’s Disease)
Current Alzheimer Research Aβ Monomers, Oligomers and Fibrils: Structural Features
Current Bioactive Compounds Risperidone Long-Acting Injection in the Treatment of First Episode Schizophrenia
Current Psychopharmacology Clustering Based Approach for Segmentation of Optic Cup and Optic Disc for Detection of Glaucoma
Current Medical Imaging Diagnostic Cardiac Catheterization in the Pediatric Population
Current Cardiology Reviews Cell-Penetrating Peptide-Mediated Topical Delivery of Biomacromolecular Drugs
Current Pharmaceutical Biotechnology Schizophrenia Patient Shows a Rare Interleukin 15 Receptor alpha Variant Disrupting Signal Transduction
Current Molecular Medicine Soluble Forms of RAGE in Human Diseases: Clinical and Therapeutical Implications
Current Medicinal Chemistry Analysis and Prediction of Myristoylation Sites Using the mRMR Method, the IFS Method and an Extreme Learning Machine Algorithm
Combinatorial Chemistry & High Throughput Screening Role of Cdk5 in Amyloid-beta Pathology of Alzheimer’s Disease
Current Alzheimer Research Current Immune Therapies of Autoimmune Disease of the Nervous System with Special Emphasis to Multiple Sclerosis
Current Pharmaceutical Design