The Effect of SLC19A3 Inhibition on the Pharmacokinetics of Thiamine

Thiamine is an essential vitamin meaning humans must consume thiamine from their diet in
order to stay healthy. Low thiamine levels can lead to adverse events. Thiamine is absorbed
in the intestine by a transporter protein. This is made by the SLC19A3 gene. The SLC19A3 gene
provides instructions for making the thiamine transporter protein, which moves thiamine into
cells. Certain drugs, like metformin and trimethoprim, have been shown to interrupt function
of the SLC19A3 gene.

Metformin is a first-line therapy for patients with Type 2 diabetes and is associated with
improvements in diabetic complications. Trimethoprim is an anti-bacterial drug that is often
prescribed to treat infections such as urinary tract infections. At different phases of this
three-cycle study, participants will be administered thiamine, thiamine with metformin, or
thiamine with trimethoprim to determine whether taking a drug and a vitamin together affects
the body's ability to absorb, distribute, and eliminate thiamine. The levels of thiamine in
the participants' blood and urine will be measured before and after taking thiamine or
thiamine in combination with metformin and trimethoprim.

Inclusion Criteria:

1. Male or female between the ages of 18-65 years old.

2. Eats a wide variety of food and willing to consume study diet (i.e. not on a specific
diet such as Atkins, Fodmap, etc.).

3. Written informed consent obtained from the subject and ability for subject to comply
with the requirements of the study.

Exclusion Criteria:

1. Subjects who are pregnant, breastfeeding, or unwilling to practice birth control
during participation in the study.

2. Self-reported severe food allergies or diet restrictions (vegans, vegetarians, Atkins,
Fodmap, etc.) that would prevent consumption of study diets.

3. Subjects with extreme obesity (BMI > 35).

4. Subjects who are smokers or have smoked in the past year and/or have smoked or
ingested THC/marijuana in the past week, or who are unwilling to comply with a 1-week
washout.

5. Subjects with any disease affecting or impairing the function of the liver, kidney or
heart.

6. Subjects with moderate to severe hypertension.

7. Subjects with diabetes mellitus, hyperthyroidism, hypothyroidism, cardiovascular
disease, glaucoma.

8. Subjects with gastrointestinal disease, gastrointestinal disorder, or gastrointestinal
surgery.

9. Subjects with known infection with HIV, Hepatitis B (HBsAg) or Hepatitis C (no
laboratory diagnostics concerning these diseases will be performed within the present
study. Volunteers who are cured of past HepC infection are eligible to participate
with doctor's approval letter).

10. Alcohol use on average > 2 servings/day or > 14 servings/wk (Serving size: 12oz
beer/4oz wine/2oz hard liquor) or self-reported binge drinking.

11. Subjects that are on vitamin B supplements or multi-vitamins or who have taken vitamin
B supplements or multi-vitamins in the past 30 days, or are not willing to comply with
a 30-day washout of vitamin B supplements.

12. Subjects with possible folate deficiency.

13. Subjects taking any other clinically significant drugs as judged by the investigator.

14. Subjects with a condition, disease, or abnormality that in the opinion of the
Investigator would compromise the safety of the patient or the quality of the data.

15. Female subjects undergoing treatment for infertility or hormone replacement therapy
(Volunteers using hormonal birth control will not be excluded).

16. Subjects who have taken antimalarials in the past 60 days.

17. Participating in another research study while participating in this research study.

18. Non-English speaking

19. Subjects with abnormal laboratory results at screening as judged by the investigator
or study physician.