Studies of Sulfur Metabolism in Humans
Condition: Metabolic Side Effects of Drugs
MeSH terms: Drug-Related Side Effects and Adverse Reactions; Metabolic Side Effects of Drugs and Substances
Study type: Interventional
Phase: Early Phase 1

Summary: 
      The study test whether the NSAID allosteric site of human sulfotransferase 1A1 (SULT1A1) is
      operative in humans. The study will test the effects of mefenamic acid (MEF) on the
      sulfonation of acetaminophen (APAP, a SULT1A1 specific substrate) and dehydroepiandrosterone
      (DHEA, a SULT2A1 substrate). If the allosteric site is active in vivo, MEF is predicted to
      result in a decrease in sulfonation of APAP (MEF inhibits SULT with high affinity (Ki = 23
      nM), and to have no effect on sulfonation of the DHEA (MEF has little or no effect on SULT2A1
      activity).
    

Detailed description: 
      No patient registries associated with this study.

      A single, therapeutic dose of acetaminophen (APAP, 1.0 g)) or dehydroepiandrosterone (DHEA,
      75 mg) is taken orally (with 375 ml of water) either alone or simultaneously with a single,
      oral, therapeutic dose of mefenamic acid (MEF, 0.75 g). In total, 5 experiments will be
      performed: 1, APAP alone; 2, DHEA alone; 3, MEF alone; 4, APAP + MEF; and 5, DHEA + MEF. Each
      experiment will be performed in duplicate. Compounds will be taken prior to eating breakfast.
      One hour later, the patient has a light breakfast (Cheerios and milk, and a cup of coffee)
      and eats normally thereafter. Urine samples are collected at 15', 30', 1 h, 2h, 3h, 4h, 5 h,
      6h, 7h, 8h, 9h, 10h, 11h, and 12h intervals following dosing. The study subject will attempt
      to completely empty their bladder at each urine-collection time point. The samples are
      weighed. A 10 ml aliquot is taken from each time point and the aliquots are stored at -20 °C.
      Samples (0.5 ml) are then transferred to nuclear magnetic resonance (NMR) tubes and NMR
      spectra are taken to assess drug metabolites in urine. Proton NMR will be performed using the
      600 MHz instrument in the Einstein facility.
    

Intervention name(s): SULT Allosteric Inhibition
Intervention type(s): Drug
Intervention description(s): A single, therapeutic dose of acetaminophen (APAP, 1.0 g)) or dehydroepiandrosterone (DHEA, 75 mg) is taken orally (with 375 ml of water) either alone or simultaneously with a single, oral, therapeutic dose of mefenamic acid (MEF, 0.75 g). In total, 5 experiments will be performed. Each experiment is performed in duplicate. Compounds are taken prior to eating breakfast. One hour later, the patient has a light breakfast and eats normally thereafter. Urine samples are collected at 15', 30', 1 h, 2h, 3h, 4h, 5 h, 6h, 7h, 8h, 9h, 10h, 11h, and 12h intervals following dosing. The samples are weighed. A 10 ml aliquot is taken from each time point and the aliquots are stored at -20 °C. Samples (0.5 ml) are then transferred to NMR tubes spectra are taken to assess drug metabolites in urine.
Intervention model: Single Group Assignment
Intervention model description: This study will involve only a single individual.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: sulfotransferase; metabolism; acetaminophen; dehydroepiandrosterone; mefenamic acid; allostery