Studies of Sulfur Metabolism in Humans

Metabolic Side Effects of Drugs Clinical Trial

Official title:

Allosteric Regulation of Cytosolic Sulfotransferases in Humans

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03383133
• Other study ID #: 2017-8685
• Status: Completed
• Phase: Early Phase 1
• Start date: January 11, 2018
• Est. completion date: February 2, 2023

Study information

• Verified date: October 2023
• Source: Albert Einstein College of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1
• Est. completion date: February 2, 2023
• Est. primary completion date: February 2, 2023
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 61 Years to 61 Years

Eligibility

Inclusion criteria:

• Gender - one male

• Age - 61 y.o.

• Healthy

• Agreed to sign the consent form

Exclusion criteria:

? None

Related Conditions & MeSH terms

• Drug-Related Side Effects and Adverse Reactions
• Metabolic Side Effects of Drugs
• Metabolic Side Effects of Drugs and Substances

Intervention

Drug:
• SULT Allosteric Inhibition
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.

Locations

Country	Name	City	State
United States	Albert Einstein Collage of Medicine	Bronx	New York

Sponsors (1)

Lead Sponsor	Collaborator
Albert Einstein College of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (13)

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.