Pharmacokinetics, Metabolism and Analgesic Effects of Flupirtine
Condition: Pain; Pharmacokinetics; Flupirtine
Study type: Interventional
Phase: Phase 1

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 UGT1A1*28 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 NAT1/NAT2, 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.
    

Intervention name(s): 100 mg flupirtine intravenous; 100 mg flupirtine per os; 400 mg flupirtine per os; induce delayed onset of muscle soreness (DOMS); electric pain measurement
Intervention type(s): Drug; Drug; Drug; Procedure; Procedure
Intervention description(s): Administration of 100 mg flupirtine intravenous (3 mg solution intravenously, 1 vial Kadadolon® inject); Administration of 100 mg flupirtine per os (1 capsule Kadadolon®); Administration of 400 mg flupirtine (1 Kadadolon® S long retard tablet); The DOMS exercise protocol consists of two sets of 50 concentric/eccentric contractions of the calf muscles of one leg with a rest of 5 min in-between. The exercise is performed 22-26 h prior to medication. For pain measurements, muscle pain is stimulated by standing on tiptoes of one leg for 30 s, which requires a constriction of the affected calf muscles. The other leg is lifted and the subjects are allowed to hold on to a table to keep their balance. The pain intensity during this stimulation is then rated by means of a 10 cm visual analogue scale (VAS). The VAS is extended from "no pain" to "intolerable pain" with a precision of 1 mm. The stimulation is repeated with the other leg. The sequence of the legs is chosen randomly.; The method has been described to be sensitive to quantify analgesic opioid effects. Painful 5 Hz sine waves electrical stimuli (increase of intensity 0.2 mA/s, from 0 to 20 mA), which predominantly activate C-fibres, will be applied via two gold electrodes placed on the medial and lateral side of the distal phalangeal joint (middle finger of the left hand as default-testing site).
During testing, subjects keep a button continuously pressed until they find the pain intolerably and interrupt the current by releasing the button. The electrical current at which this occurred is defined as pain tolerance, the target parameter of this pain model. Each value of pain tolerance is the median of five subsequent measurements obtained at an interval of 1 min.
Other intervention name(s): 1 vial Kadadolon® inject; 1 capsule Kadadolon®; 1 Kadadolon® S long retard tablet
Intervention MeSH terms: Flupirtine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science