Variability of Sulfotransferase 1A1 Activity in Humans: an Approach to Improve Predictive Drug Response - Part I: Analysis of Intraindividual Variation in Healthy Adults

An open-label, single centre, nonrandomized clinical study in healthy volunteers, with intervention over a 13---week period. After written informed consent, subjects will undergo screening evaluations (Visit 1). One week after visit 1, subjects who meet the selection criteria will enter a run---in period of 8 weeks where participants will receive paracetamol 1g tablet and collect a blood sample at monthly intervals (visits 2, 3 and 4). A final visit for safety assessment will take place at week 13 (visit 5). Blood samples will be used to quantify P, PG e PS.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Paracetamol

Detailed Description

To be able to predict efficacy and adverse reactions involving compounds metabolized by sulfonation, the investigators need more information on SULTs. Studies of in vivo sulfonation in humans are lacking, although they are of key importance in assessing the functional consequences of individual variation. In our current study, the investigators will start by developing an HPLC method of quantifying SULT1A1 activity using paracetamol as probe substrate and studying intraindividual variation in healthy adults. Advantages of using paracetamol as a probe substrate for in vivo phenotyping of SULT1A1 include: wide safety margin for in vivo use, easy and ready administration of the drug, significant metabolism by the enzyme of interest, short half---life, linear pharmacokinetics over a wide concentration range and a limited number of metabolites, quantifiable in plasma.15,24 In a subsequent study, the investigators plan to study interindividual variation in a larger sample, including subjects with chronic disease and on medication.The investigators expect to provide a valuable new tool to explore the clinical significance of variation of SULT1A1 activity, the most important SULT on drug metabolism.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• Portugal
  • Lisboa, Portugal, 1500-650
    • Hospital da Luz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy males and females, over 18 years of age,
• Informed of the nature of the study and giving written informed consent,
• Report no significant diseases during screening,
• Have normal CBC, renal function and liver enzymology,
• Have no contraindication for paracetamol,
• Be on no regular medical treatment, except for contraceptives,
• Be able to communicate effectively with study personnel.

Exclusion Criteria:

• Hypersensitivity or idiosyncratic reaction to paracetamol,
• Intake of any medication, except for contraceptives, within 14 days before start of the study,
• Pregnancy or breastfeeding,
• BMI <18 kg/m2,
• Participation in a clinical study of any investigational product 1 month prior to visit 1 or during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: open---label; An open---label, single centre, nonrandomized clinical study in healthy volunteers, with intervention over a 13---week period.

Drug: Paracetamol; Volunteers will be screened at visit 1, and if they meet the inclusion/exclusion criteria they will receive the intervention at visit 2. At visit 2, complying subjects will receive a tablet containing 1 gram of paracetamol and have a blood sample collected 2 hours after administration; these procedures will be repeated on 2 more occasions (visits 3 and 4). The subjects will come for 5 visits during the study. Visit 1 and 2 must occur within 7 days of each other, visits 2, 3 and 4 will be four weeks (± 3 days) apart and visit 5 scheduled four weeks (± 3 days) after visit 4.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
- Coefficient of variation of paracetamol sulfonation index (PSI), a ratio between the measured plasma concentrations of paracetamol sulfate (PS) and PS+ paracetamol glucoronide (PG) + paracetamol (P)	9 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Reproductibility, sensitivity and accuracy of the HPLC method (human samples will be used to validate the method);	9 months
Relationships between PSI and subject characteristics (gender, age, genotype, smoking status, caffeine consumption, alcohol consumption, oral contraceptive use);	9 months
Relationship between SULTA1 expression and predose and postdose metabolic profiles;	9 months
Association between SULT1A1 genotype and SULT1A1 expression (optional);	9 months
Association between PSI and SULT1A1 genotype (optional).	9 months

Collaborators and Investigators

• Sponsor: Hospital da Luz, Portugal
• Collaborators: Universidade Nova de Lisboa
• Investigators: Principal Investigator: Natália Marto, MD, Hospital da Luz

Publications and helpful links

General Publications

• Marto N, Morello J, Antunes AMM, Azeredo S, Monteiro EC, Pereira SA. A simple method to measure sulfonation in man using paracetamol as probe drug. Sci Rep. 2021 Apr 27;11(1):9036. doi: 10.1038/s41598-021-88393-3.

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2017
• Primary Completion (Actual): January 31, 2018
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: May 25, 2017
• First Submitted That Met QC Criteria: June 7, 2017
• First Posted (Actual): June 9, 2017

Study Record Updates

• Last Update Posted (Actual): August 25, 2021
• Last Update Submitted That Met QC Criteria: August 24, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: HLUZ_001_2016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No