Membrane transporters are steadily gaining recognition as important factors in the absorption, distribution, metabolism, and excretion of many nutrients, as well as many xenobiotic compounds such as prescribed medicines, toxic metals, many agricultural chemicals.
The combination of polypharmacy and the current regulatory requirements, necessitate all new drugs be evaluated for their impact on a predetermined range of transporters, and their proposed mechanisms of action ie as substrates or inhibitors. Metformin is the universal probe for evaluating potential thiamine transporter-mediated drug-drug interactions as it functions as both a substrate and an inhibitor.
Metformin is the fourth mostly commonly prescribed medicine globally, consequently its side effects such as negative impacts on various nutrients, affect a significant percentage of the global population – certainly many millions of people.
Metformin improves insulin resistance by increasing glucose uptake into muscle and adipose tissue and by decreasing liver-based gluconeogenesis.
Thiamine cannot be produced in the body and therefore must be obtained via intestinal absorption from exogenous sources such as food and gut microbiota production. Thiamine’s availability is determined by adequacy of intake, magnesium availability, and degree of xenobiotic interference.
Thiamine is essential for metabolism to proceed, and functions by regulating molecular oxygen homeostasis and mitochondrial ATP production. Functions include carbohydrate metabolism ie generating energy, glucose metabolism, being a cofactor for ATP production (primary source of energy for cells), production of neurotransmitters, lipid metabolism, amino acid modification, and neuromodulation.
Thiamine deficiency causes regionally selective neuronal death, mitochondrial dysfunction, energy shortage, chronic oxidative stress, altered mental status (confusion, lethargy and apathy), altered oculomotor dysfunction (involuntary rhythmic and/or unco-ordinated eye movements), altered ataxia of stance and gait (ranging from mild imbalance and unsteadiness to wide-based shuffling to inability to sit or stand). Astrocytes are among the first cells to be affected by thiamine deficiency in advance of neuronal cell death (MedNut Mail 2022-06-29 - https://medicationsandnutrition.online/astrocytes-and-pharmaconutrition/).
Thiamine deficiency manifests as nausea, vomiting, constipation, loss of appetite, altered swallow capability, abdominal discomfort, depression, fatigue, confusion, disturbed sleep, irritability, agitation, lethargy – this combination is so common, especially in the elderly, as to not be useful for identifying thiamine deficiency specifically.
Key thiamine transporters include -
- THTR1 - from gut to epithelia, skeletal muscle, nervous system, eye, placenta, kidney,
- THTR2 – from gut to epithelia, adipose tissue, breast tissue, liver, lymphocytes, spleen, gallbladder, placenta, pancreas, brain,
- OCT1 - blood to liver,
- OCT2 - blood to kidney,
- OCT3 - blood to muscles,
- MATE1/2 - kidney to urine,
- assorted others.
Blood tests for thiamine status are unlikely to be reliable as thiamine transport is inhibited and consequently thiamine can neither enter nor exit relevant organs and cells. There is evidence that some drugs inhibit transporters for 6 hours however I have been unable to ascertain metformin’s duration of inhibition. Therefore, management strategies to consider would include –
- checking thiamine status and ascertaining whether blood levels are acceptable or high – and then clarifying whether any prescribed medications are inhibiting any relevant transporters;
- determining duration of metformin prescription. If it is 6+ months then perhaps a regular thiamine intervention be considered and administered at a different time from metformin. For example, if metformin is administered at 08:00 and 16:00 (Aged Care hours) then thiamine intervention could be administered at lunchtime (thiamine can also inhibit its transporters);
- if lethargy and/or drowsiness is interfering with food intake then suggest a thiamine and magnesium intervention and administered at a different time from metformin.
What actions will you initiate when metformin is one of the prescribed medications, will you –
- clarify thiamine status and then recommend a thiamine intervention and try and identify a suitable time for its administration?
- clarify magnesium status and then recommend a magnesium intervention and try and identify a suitable time for its administration?
- try and ascertain thiamine status based on expressed signs and symptoms?
Transporter-mediated drug-nutrient interactions are adding an extra layer of complexity to managing drug-nutrient interactions. Given thiamine’s importance are we already seeing the lack of thiamine availability being expressed but not recognizing it?
Medical History with Nutritional Aspect
Biochemistry with Nutritional Aspect
Medications That May Adversely Affect Nutritional Status
Summary of medications, nutrients and transporters matrix
Comments – medication and nutrition impacts (direct and indirect) only
Recent relevant biochemistry indicates -
- low Hb - associated with increased risk of falls, and poor appetite; Somac prescription is a likely contributor;
- elevated MCV - advisable to check B12 levels; Somac associated with decreasing B12 status.
Currently prescribed 5 medications that alter glycaemia, being lactulose, Lasix, Lipitor, paracetamol and Targin.
Currently prescribed 10 medications that include nausea and diarrhoea as side effects.
Currently prescribed 6 medications that include decreased appetite and altered sense of taste as side effects.
Calcium carbonate requires gastric acidity for absorption however somac prescribed therefore advisable to consider calcium citrate which does not require gastric acidity for absorption.
Chronic use of lactulose may promote excessive loss of water and electrolytes, especially potassium, and their regular monitoring recommended.
Lasix increases urinary excretion of calcium, magnesium, potassium, sodium and thiamine.
Dietary levels of caffeine intake in conjunction with paracetamol inhibit antinocieception.
Concurrent ingestion of paracetamol and iron resulted increased rate of iron absorption and decreased extent of drug absorption; the authors advise drug and iron to be administered at different times from each other.
Perinodopril impairs zinc status.
Regular monitoring sodium levels recommended whilst pristiq prescribed.
Somac decreases B12, vitamin C, magnesium, zinc and iron absorption, may decrease calcium absorption, and decreases thiamine availability.
Currently prescribed vitamin D (1 tab/day). Advisable to check vitamin D levels and if still low then review current vitamin D intervention.
There is increasing evidence that proton pump inhibitors such as somac significantly impair magnesium absorption. Magnesium deficiency manifests as confusion, disorientation, personality changes, loss of appetite, depression, muscle cramps, tingling, numbness, hypertension, cardiac dysrhythmia, seizures. Magnesium is an intracellular ion therefore serum levels are unlikely to detect early depletion of status. Cellular magnesium status is unknown whilst magnesium levels within acceptable range however if magnesium levels are low then typically indicates significant cellular depletion. Currently prescribed Somac therefore advisable to clarify magnesium status and if low then intervention recommended, however oral magnesium intervention may be ineffective whilst there is acid inhibition.
Statins such as lipitor interfere early in the cholesterol metabolic pathway and consequently decrease -
- conversion of sun to vitamin D - vitamin D intervention recommended;
- production of CoQ10 - important in cellular energy production; CoQ10 intervention recommended;
- DHEA production - low DHEA associated with increased risk of metabolic syndrome.
Advisable to clarify cholesterol status and if low then review necessity for ongoing prescription of Lipitor.
- regular aperients prescribed,
- oral PRN aperient prescribed,
- no Nurse Initiated interventions administered.
Staff advise Mr AGL has a diminishing appetite and that he recently had an infected toe that required antibiotic intervention; he also has poor dentition.
Mr AGL is a pale, frail, big-framed man with a flat demeanour, thyroidy eyes, cold hands, and who was sitting hunched in his room. Mr AGL did not always answer my questions but did agree he had lost weight, and that he prefers desserts to main course. Mr AGL agreed he was cold so I wrapped a blanket around him and told him that when people don't eat enough then they feel cold.
Mr AGL has lost weight since early 2015.
Since Mr AGL is pale, advisable to check iron levels and if low then short term (90-120 days) intervention recommended however evidence indicates iron deficiency anaemia is unlikely to resolve whilst a proton pump inhibitor is prescribed.
Mr AGL’s diagnoses include chronic pain - nutritional factors that may be useful to consider in pain management include
- vitamin D - current intervention may not be adequate to attain adequate range. Evidence indicates increasingly brittle pain control with decreasing vitamin D levels. Currently prescribed Lipitor which decreases vitamin D status. Advisable to check vitamin D levels and if still low then review current vitamin D management strategy
- vitamin C - pain increases the reactive substances (formerly Reactive Oxygen Species) within cells. Vitamin C is important in quenching reactive substances and if there is insufficient vitamin C then cell status becomes compromised and the cells typically die which also causes pain. Vitamin C is not considered part of the pain management armament however it won't cause harm and evidence suggests it may confer benefit. Currently prescribed Somac which decreases conversion of vitamin C to its active form.
- low B12 exacerbates elevated TNF- α which is an inflammatory response marker; elevation of the inflammatory response can include a pain response and currently prescribed Somac therefore advisable to clarify B12 status.
- magnesium – proposed mechanism magnesium blocks the NMDA receptor channels in the spinal cord and thus limits the influx of calcium ie reduces the risk of excitotoxicity and consequent exacerbation of pain. Currently prescribed Lasix and Somac which decrease magnesium absorption. Advisable to clarify magnesium status and if low then intervention recommended however magnesium absorption likely to be compromised by Somac prescription.
What else would you include?