Ignite Creation Date:
2024-05-06 @ 12:50 AM
Last Modification Date:
2024-10-26 @ 10:55 AM
Study NCT ID:
NCT01676246
Status:
COMPLETED
Last Update Posted:
2012-08-30
First Post:
2012-08-28
Brief Title:
Pharmacokinetics Metabolism and Analgesic Effects of Flupirtine
Sponsor:
University Medicine Greifswald
Organization:
University Medicine Greifswald
Study Overview
Official Title:
Pharmacokinetics Metabolism and Analgesic Effects of Flupirtine After Intravenous Single Dose and Chronic Oral Administration in Healthy Subjects Genotyped for NAT2 UGT1A1 and GSTP1
Status:
COMPLETED
Status Verified Date:
2012-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Flupirtine is metabolized in-vitro via carbamate cleavage and N acetylation to glucuronides and mercapturic acid derivatives The formation of reactive toxic intermediate products may be influenced by genetic polymorphisms of the involved conjugative metabolic pathways So the purpose of this study is to measure pharmacokinetics metabolism and analgesic effects of flupirtine in dependence on the function of NAT2 UGT1A1 and GSTP1
Detailed Description:
Flupirtine is a centrally acting analgesic drug Its mechanism of action differs obviously from opiates because flupirtine antagonizes the morphine-induced tail phenomenon in mice in relatively low doses The drug exerts no relevant anesthetic activity and it has only slight inhibitory effect on prostaglandin formation in animals As major action mechanism activation of descending noradrenergic neuronal pathways is discussed thereby inhibiting afferent nociceptive stimuli on spinal subcortical and cortical brain areas Recently has been shown that flupirtine exhibits functional NMDA receptor antagonistic properties by selective opening the neuronal potassium channel
The anticonvulsant drug retigabine which chemical structure only slightly differs from flupirtine aromatic ring instead of the pyrimidine ring is subjected to intensive glucuronidation and N-acetylation in man In-vitro retigabine is a substrate of the recombinant uridine glucoronosyl transferase UGT 1A1 1A3 1A4 and 1A9 Disposition of retigabine however was not influenced by the frequent UGT1A128 polymorphism Gilbert-Meulengracht syndrome whereas the polymorphism of the N-acetyltransferase 2 NAT2 resulted in significant changes in retigabine disposition
Similar to retigabine the carbamate group of flupirtine is hydrolyzed by carboxyl esterases The decarbamylated product undergoes N-acetylation to form the major metabolite D13223 This acetylation is catalyzed in-vitro both by recombinant human NAT2 and NAT1 Furthermore relatively stable quinone diimines for flupirtine and D13223 as catalyzed by peroxidases were detectable in in-vitro experiments After repeated oral administration of flupirtine in man quinone diimines and glutathione adducts of them in the form of mercapturic acid conjugates were detected
Therefore we hypothesize that highly reactive diimine radicals may appear as intermediates which are detoxified by conjugation with glutathione via a glutathione S-transferase GST Diimine intermediates are known to have high cell toxicity genotoxicity and carcinogenicity as shown for the intermediates of acetaminophen By analogy to acetaminophen the GSTP1 might be the isoform that is involved also in detoxification of flupirtine intermediates
According to our hypothesis the net appearance of toxic intermediates with diimine structure in hepatocytes is dependent on the activity of NAT1NAT2 UGTs and GSTP1 Because NAT2 UGT1A1 and GSTP1 are highly polymorphic enzymes the risk of flupirtine hepatotoxicity may be dependent on the genotype of the subjects that are treated with the drug
Our clinical study was initiated to confirm whether polymorphisms of NAT2 UGT1A1 and GSTP1 may significantly influence disposition and analgesic effect of flupirtine and whether the genetic background is of risk for the appearance of toxic intermediates and its stable terminal conjugates
The anticonvulsant drug retigabine which chemical structure only slightly differs from flupirtine aromatic ring instead of the pyrimidine ring is subjected to intensive glucuronidation and N-acetylation in man In-vitro retigabine is a substrate of the recombinant uridine glucoronosyl transferase UGT 1A1 1A3 1A4 and 1A9 Disposition of retigabine however was not influenced by the frequent UGT1A128 polymorphism Gilbert-Meulengracht syndrome whereas the polymorphism of the N-acetyltransferase 2 NAT2 resulted in significant changes in retigabine disposition
Similar to retigabine the carbamate group of flupirtine is hydrolyzed by carboxyl esterases The decarbamylated product undergoes N-acetylation to form the major metabolite D13223 This acetylation is catalyzed in-vitro both by recombinant human NAT2 and NAT1 Furthermore relatively stable quinone diimines for flupirtine and D13223 as catalyzed by peroxidases were detectable in in-vitro experiments After repeated oral administration of flupirtine in man quinone diimines and glutathione adducts of them in the form of mercapturic acid conjugates were detected
Therefore we hypothesize that highly reactive diimine radicals may appear as intermediates which are detoxified by conjugation with glutathione via a glutathione S-transferase GST Diimine intermediates are known to have high cell toxicity genotoxicity and carcinogenicity as shown for the intermediates of acetaminophen By analogy to acetaminophen the GSTP1 might be the isoform that is involved also in detoxification of flupirtine intermediates
According to our hypothesis the net appearance of toxic intermediates with diimine structure in hepatocytes is dependent on the activity of NAT1NAT2 UGTs and GSTP1 Because NAT2 UGT1A1 and GSTP1 are highly polymorphic enzymes the risk of flupirtine hepatotoxicity may be dependent on the genotype of the subjects that are treated with the drug
Our clinical study was initiated to confirm whether polymorphisms of NAT2 UGT1A1 and GSTP1 may significantly influence disposition and analgesic effect of flupirtine and whether the genetic background is of risk for the appearance of toxic intermediates and its stable terminal conjugates
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None