Effects of Sucralose on Drug Absorption and Metabolism (The SweetMeds Study)

Background:

Consumption of non-nutritive sweeteners (NNS) has dramatically increased worldwide and is
more prevalent in women than men. Similarly, obesity rates have continued to rise, most
notably in minorities. Since NNS consumption has been linked to obesity, we propose studying
NNS effects specifically in minority women.

NNS are frequently consumed in combination with prescription medications. This necessitates
the study of possible NNS-drug interactions. The hypothesis that NNS may affect drug
absorption and metabolism is based on a rodent study. In 2008, Abou-Donia et al reported that
sucralose increased the activity of P-glycoprotein (P-gp), a membrane transporter involved in
absorption and distribution of a wide range of pharmacologic compounds, and CYP3A, a
cytochrome P-450 enzyme important to the first-pass metabolism of many drugs.

So far, NNS effects in clinical studies were mostly observed after acute (one time) or short
term exposure. For example, we and others found increased incretin and insulin concentrations
in response to sucralose alone or in combination with acesulfame-potassium prior to a glucose
load. The effects were most pronounced in obese African American women. We also found
upregulation of inflammatory cytokines in subcutaneous fat biopsies of obese individuals who
reported consumption of NNS compared to non-consumers. Whether these hormonal and tissue
responses persist after prolonged exposure needs to be investigated. NNS have also been shown
to influence the microbial composition of the oral cavity and the gut. However, most data
were generated in mice and do not exist in humans.

Aims:

Primary Aim: To determine the effects of sucralose (4 mg/kg/day) administered to overweight
and obese minority women for 28 days on drug metabolism using digoxin and midazolam as probes
for P-glycoprotein and CYP3A, respectively.

Secondary Aims: To investigate the effects of sucralose on

1. glucose metabolism and incretin secretion

2. lipid metabolism

3. intestinal microflora

Methods:

The study consists of 3 periods. In the first period (run-in, 7 days), participants will be
instructed to avoid all NNS (including NNS in cosmetics or health care products). During the
second and third periods (14 days each), participants will be randomized to consume either
sucralose containing capsules (4 mg/kg/day) or placebo. At the end of each period, the
following measurements will be obtained during an overnight hospitalization:

1. Serial measurements of plasma concentrations of midazolam and digoxin for 24 hours
following a single oral dose of each drug

2. Frequently sampled 2-hour oral glucose tolerance test (OGTT) to measure glucose,
insulin, C-peptide, GLP-1, and other gut hormones.

At the end of P1 (run-in, no intervention) and after P3 (sucralose exposure x 4 weeks),
subcutaneous fat biopsies will be performed. Stool samples will be obtained throughout.

- INCLUSION CRITERIA:

1. Age: between 18 and 60 years

2. Female adults who self-identify as Hispanic and/or Black

3. Body weight greater than 50 kg (110 lb)

4. Body mass index between 25 kg/m^2 and 40 kg/m^2

5. Consumption of less than or equal to one 12-ounce beverage sweetened with NNS per
month or food equivalent

6. Healthy with no known active medical condition or illness that requires drug
treatment

7. Able and willing to consume approximately 4 mg/kg sucralose daily or placebo in
form of capsules for

4 weeks

8. Able and willing to avoid eating grapefruit, parsnips, celery, drinking grapefruit
juice or sodas containing quinine (e.g. tonic water) during the study

9. Able and willing to collect stool specimens

10. Able and willing to consume digoxin and midazolam during study visits

EXCLUSION CRITERIA:

1. Current use of prescription or non-prescription medication(s), herbal medications and
oral contraceptives are also excluded. Certain exceptions are permitted, including
vitamins. Other medications may be permitted at the discretion of the investigators.

2. Diabetes (fasting blood glucose of 126 mg/dl or higher, or 2-hour blood glucose of 200
or higher on OGTT)

3. Taken medications that affect blood sugar in the past 3 months or that include
antibiotics

4. GI history, at the discretion of the investigators

5. Known allergy, sensitivity, or other contraindication to study procedures

6. ALT or AST more than 1.5 times the upper limit of normal

7. Abnormal thyroid function or abnormal serum electrolytes & minerals (specifically
potassium, calcium, and magnesium)

8. Narrow angle glaucoma or untreated open angle glaucoma

9. Regular use of alcohol (more than 1 drink per day) or drug use

10. History of cardiac abnormalities, especially arrhythmia

11. Unable or unwilling to cooperate with study procedures

12. Psychiatric or cognitive disorder that will, in the opinion of the investigators,
limit the subject's ability to provide informed consent, or to comply with study
procedures

13. Pregnant, planning to become pregnant or lactating (digoxin and midazolam are Category
C and D medications, respectively).