Studies of Sulfur Metabolism in Humans

NCT03383133 | Completed Early Phase 1 FDA Drug

• 1 other identifier: 2017-8685
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief 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).

Conditions

Metabolic Side Effects of Drugs

Keywords

sulfotransferase; metabolism; acetaminophen; dehydroepiandrosterone; mefenamic acid; allostery

Outcome Measures

Primary Outcomes (1)

• Acetaminophen and Dehydroepiandrosterone Conjugates

  Proton NMR Signals will be used to quantitate conjugates of acetaminophen and dehydroepiandrosterone in urine.

  15min, 30min, 1hr, 2hr, 3hr, 4hr, 5hr, 6hr, 7hr, 8hr, 9hr, 10hr, 11hr, and 12hr following administration.

Study Arms (1)

SULT Allosteric Inhibition

EXPERIMENTAL

A single, therapeutic dose of acetaminophen (1.0 g)) or dehydroepiandrosterone (75 mg) is taken orally (with 375 ml of water) either alone or simultaneously with a single, oral, therapeutic dose of mefenamic acid (0.75 g).

Drug: SULT Allosteric Inhibition

Interventions

SULT Allosteric Inhibition DRUG

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.

SULT Allosteric Inhibition

Eligibility Criteria

• Age: 61 Years - 61 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Gender - one male
• Age - 61 y.o.
• Healthy
• Agreed to sign the consent form

You may not qualify if:

• ● None

Sponsors & Collaborators

• Albert Einstein College of Medicine: lead

Study Sites (1)

Albert Einstein Collage of Medicine

The Bronx, New York, 10461, United States

Location

Related Publications (13)

• Falany JL, Macrina N, Falany CN. Regulation of MCF-7 breast cancer cell growth by beta-estradiol sulfation. Breast Cancer Res Treat. 2002 Jul;74(2):167-76. doi: 10.1023/a:1016147004188.

  PMID: 12186377 BACKGROUND

• Parker CR Jr. Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging. Steroids. 1999 Sep;64(9):640-7. doi: 10.1016/s0039-128x(99)00046-x.

  PMID: 10503722 BACKGROUND

• Cook IT, Duniec-Dmuchowski Z, Kocarek TA, Runge-Morris M, Falany CN. 24-hydroxycholesterol sulfation by human cytosolic sulfotransferases: formation of monosulfates and disulfates, molecular modeling, sulfatase sensitivity, and inhibition of liver x receptor activation. Drug Metab Dispos. 2009 Oct;37(10):2069-78. doi: 10.1124/dmd.108.025759. Epub 2009 Jul 9.

  PMID: 19589875 BACKGROUND

• Visser TJ. Role of sulfation in thyroid hormone metabolism. Chem Biol Interact. 1994 Jun;92(1-3):293-303. doi: 10.1016/0009-2797(94)90071-x.

  PMID: 8033262 BACKGROUND

• Eisenhofer G, Coughtrie MW, Goldstein DS. Dopamine sulphate: an enigma resolved. Clin Exp Pharmacol Physiol Suppl. 1999 Apr;26:S41-53.

  PMID: 10386253 BACKGROUND

• Swann J, Murry J, Young JA. Cytosolic sulfotransferase 1A1 regulates HIV-1 minus-strand DNA elongation in primary human monocyte-derived macrophages. Virol J. 2016 Feb 24;13:30. doi: 10.1186/s12985-016-0491-9.

  PMID: 26906565 BACKGROUND

• Yalcin EB, More V, Neira KL, Lu ZJ, Cherrington NJ, Slitt AL, King RS. Downregulation of sulfotransferase expression and activity in diseased human livers. Drug Metab Dispos. 2013 Sep;41(9):1642-50. doi: 10.1124/dmd.113.050930. Epub 2013 Jun 17.

  PMID: 23775849 BACKGROUND

• Wang T, Cook I, Leyh TS. The NSAID allosteric site of human cytosolic sulfotransferases. J Biol Chem. 2017 Dec 8;292(49):20305-20312. doi: 10.1074/jbc.M117.817387. Epub 2017 Oct 16.

  PMID: 29038294 BACKGROUND

• Riches Z, Stanley EL, Bloomer JC, Coughtrie MW. Quantitative evaluation of the expression and activity of five major sulfotransferases (SULTs) in human tissues: the SULT "pie". Drug Metab Dispos. 2009 Nov;37(11):2255-61. doi: 10.1124/dmd.109.028399. Epub 2009 Aug 13.

  PMID: 19679676 BACKGROUND

• Nagar S, Walther S, Blanchard RL. Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2, and *3 are associated with altered enzymatic activity, cellular phenotype, and protein degradation. Mol Pharmacol. 2006 Jun;69(6):2084-92. doi: 10.1124/mol.105.019240. Epub 2006 Mar 3.

  PMID: 16517757 BACKGROUND

• Falany CN, Vazquez ME, Kalb JM. Purification and characterization of human liver dehydroepiandrosterone sulphotransferase. Biochem J. 1989 Jun 15;260(3):641-6. doi: 10.1042/bj2600641.

  PMID: 2764897 BACKGROUND

• Cook I, Wang T, Falany CN, Leyh TS. The allosteric binding sites of sulfotransferase 1A1. Drug Metab Dispos. 2015 Mar;43(3):418-23. doi: 10.1124/dmd.114.061887. Epub 2014 Dec 22.

  PMID: 25534770 BACKGROUND

• Vietri M, De Santi C, Pietrabissa A, Mosca F, Pacifici GM. Inhibition of human liver phenol sulfotransferase by nonsteroidal anti-inflammatory drugs. Eur J Clin Pharmacol. 2000 Apr;56(1):81-7. doi: 10.1007/s002280050725.

  PMID: 10853883 BACKGROUND

MeSH Terms

Conditions

Metabolic Side Effects of Drugs and Substances

Condition Hierarchy (Ancestors)

Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders

Study Officials

• Thomas S Leyh, Ph. D.

  The Albert Einstein College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study will involve only a single individual.

Study Record Dates

• First Submitted: December 19, 2017
• First Posted: December 26, 2017
• Study Start: January 11, 2018
• Primary Completion: February 2, 2023
• Study Completion: February 2, 2023
• Last Updated: October 27, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)