Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)

Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy

DIFFERENCES AMONG FOOD CHOICE AND MOTIVES BETWEEN GENDERS IN WHITWORTH UNIVERSITY UNDERGRADUATES

I. Fetty, A. Suhre, P. Weisenhaus, W. M. Silvers Whitworth University, Spokane, WA Food choice and factors that influence food choice have been documented between genders. PURPOSE: The purpose of this study was to evaluate the differences in food choice and the factors that influence food choice between genders within a traditional undergraduate population. The research hypothesis was that there would be an observable difference in food choice and factors that influence food choice between women (W) and men (M). METHODS: Full-time undergraduate students (18-24 years old) were identified as the target population. An email was sent to randomly selected students, which invited them to participate. Emails were also distributed to various departments in the undergraduate population. Ultimately, 130 eligible respondents (68 women, 62 men) volunteered for participation. The survey prompted participants to select the frequency in which they ate certain food groups in a week; participants were then asked to choose the factor that most influenced that choice. Means and standard deviations were calculated as measures of central tendency and variance for each of the dependent variables. An independent groups t-test (p ≤ 0.05) was utilized to determine significant differences between dependent variables. RESULTS: There were statistically significant differences between women and men for animal-based protein intake frequency (W: 2.46 ± 1.94 servings/week, M: 1.40 ± 0.99 servings/week, p = 0.000), animal-based dairy (W: 4.29 ± 2.17 servings/week, M: 3.16 ± 2.17 servings/week, p = 0.004), and plant-based dairy (W: 4.96 ± 2.28 servings/week, M: 6.95 ± 1.88 servings/week, p= 0.000). Therefore, the research hypothesis was accepted. CONCLUSION: Overall, there was a significant difference between genders in animal-based protein, animal-based dairy, and plant-based dairy intake frequency. Sensory appeal and health were cited as the most important factors that influenced food choice. However, the survey questions did not elucidate further rationale that may have impacted specific food choices in the sample population. Future research in this area could benefit from a more robust question set that addresses the reasoning for food selection

Neurochemical Metabolomics Reveals Disruption to Sphingolipid Metabolism Following Chronic Haloperidol Administration

Haloperidol is an effective antipsychotic drug for treatment of schizophrenia, but prolonged use can lead to debilitating side effects. To better understand the effects of long-term administration, we measured global metabolic changes in mouse brain following 3 mg/kg/day haloperidol for 28 days. These conditions lead to movement-related side effects in mice akin to those observed in patients after prolonged use. Brain tissue was collected following microwave tissue fixation to arrest metabolism and extracted metabolites were assessed using both liquid and gas chromatography mass spectrometry (MS). Over 300 unique compounds were identified across MS platforms. Haloperidol was found to be present in all test samples and not in controls, indicating experimental validity. Twenty-one compounds differed significantly between test and control groups at the p < 0.05 level. Top compounds were robust to analytical method, also being identified via partial least squares discriminant analysis. Four compounds (sphinganine, N-acetylornithine, leucine and adenosine diphosphate) survived correction for multiple testing in a non-parametric analysis using false discovery rate threshold < 0.1. Pathway analysis of nominally significant compounds (p < 0.05) revealed significant findings for sphingolipid metabolism (p = 0.02) and protein biosynthesis (p = 0.03). Altered sphingolipid metabolism is suggestive of disruptions to myelin. This interpretation is supported by our observation of elevated N-acetylaspartylglutamate in the haloperidol-treated mice (p = 0.004), a marker previously associated with demyelination. This study further demonstrates the utility of murine neurochemical metabolomics as a method to advance understanding of CNS drug effects