Location: Obesity and Metabolism Research
Project Number: 2032-51530-025-035-R
Project Type: Reimbursable Cooperative Agreement
Start Date: Oct 1, 2017
End Date: Apr 30, 2022
Objective:
Recent findings suggest that metformin and other medications commonly used in the overwieght/obese population, can inhibit SLC19A3-mediated intestinal absorption of thiamine resulting in a previously unrecognized drug-vitamin interactions. This drug-vitamin interaction can contribute to thiamine deficiency associated with various diseases present in the obese population, including metformin-induced hyperlactatemia and lactic acidosis. At UCSF, efforts will be made to understand the scope of compound classes that can interact with this transporter, and evaluate their efficacy in a humanized mouse model in collaboration with Tufts University. At the WHNRC, targeted profiling of B1 vitamers will be used to evaluate impact on thiamine uptake and metabolism and the variance of this response in healthy individuals, while metabolomics will be used determine if a pre-deficiency metabolic signature exists which reflects a reduction in the activity of enzymes dependent on thiamine pyrophosphate (TPP), the active metabolite of thiamine.
Approach:
To assess the variability in individual metformin-thiamine interactions, thiamine vitamer pharmacokinetics will be characterized in healthy volunteers.
Aim 1. Using a randomized crossover study design in healthy volunteers, (a) determine the effects of metformin on the absorption and disposition of thiamine and its major metabolites and (b) explore metabolic signatures reflecting the activity of TPP-dependent enzymes following administration of thiamine, metformin and thiamine plus metformin. In particular, we will determine the pharmacokinetic properties of thiamine, and its two major metabolites, TMP (thiamine monophosphate), and TPP in healthy volunteers treated with thiamine (orally) alone and thiamine plus metformin. Key metabolites and metabolic ratios associated with TPP-dependent enzymes will be measured.
