Does Vitamin D Have Drug Interactions?
In our latest question and answer, the pharmacist discusses potential drug interactions involving vitamin D.
Are there any drug interactions with vitamin D? I am particularly concerned with Effexor (venlafaxine).
Potential drug interactions concerning Vitamin D are not well studied and there is a definitive lack of published information on the subject. Most drug information resources cite very few interactions or even none at all.
Nevertheless, as vitamin D is one of the most popular over the counter supplements, with sales over $900 million in 2017 alone, it would be prudent to further investigate whether or not adding it to our daily regimen will affect any prescription medication we may be taking.
Recently published research, such as a 2013 study published in the journal 'Nutrition in Clinical Practice', has found that there may be fairly significant interactions with vitamin D and further study is surely warranted.
Overall, there does appear to be a risk of vitamin D affecting the metabolism of certain drugs, but how severe this effect may be on an individual isn't well known. Further on, I discuss these potential interactions in-depth.
There is a lack of data regarding drug interactions with vitamin D. Several studies point to some possibilities, but the severity of them isn't known.
What Is Vitamin D?
Vitamin D is a fat-soluble vitamin, which our bodies naturally produce in response to sunlight. It is responsible for numerous functions in the body, perhaps most importantly, calcium and phosphate balance which is necessary for normal bone growth and mineralization. Inadequate vitamin D is strongly linked to an increased risk in fractures.
A severe deficiency of vitamin D can cause rickets and osteomalacia, a softening of the bones. Additionally, low vitamin D levels have been associated with all sorts of maladies, including :
- Cardiovascular events
- Mental health disorders (e.g. depression)
Due to the importance of adequate levels of vitamin D intake, foods, such as milk and cereal, are often fortified with it. It can also be found naturally in other foods such as fish and eggs.
Additionally, due to concerns with skin cancer and lack of sunlight at various times throughout the year, vitamin D supplementation may be necessary.
In fact, the American Academy of Dermatology recommends avoiding sunlight and getting vitamin D from food or supplements:
The AAD recommends getting vitamin D from a healthy diet that includes foods naturally rich in vitamin D, foods and beverages fortified with vitamin D, and/or vitamin D supplements.
Vitamin D intake recommendations vary by organization.
- Ages 1-70: 600 IU daily
- Over 70: 800 IU daily
The National Osteoporosis Foundation recommends:
- Aged Under 50: vitamin D 400 IU to 800 IU daily
- Aged Over 50: 800 IU to 1000 IU daily
The North American Menopause Society recommendations are the same as the National Osteoporosis Foundation.
There are a variety of tests available to measure vitamin D levels in the body. Specifically what is measured is 25-hydroxyvitamin D.
For the vast majority of individuals, a level between 20 ng/mL and 30 ng/mL is considered a safe and sufficient level to prevent bone related issues and other negative conditions. Levels over 30 ng/mL are not thought to confer additional health benefits.
It is possible to get too much vitamin D, but it is extremely unlikely if taking recommended doses. Signs of toxicity don't typically start until levels are >200 ng/mL.
Vitamin D is a fat-soluble vitamin, which our bodies naturally produce in response to sunlight. Among other things, it is necessary for normal bone growth and a lack of vitamin D is associated with fractures. For most individuals, supplementation of vitamin D is necessary to reach daily intake recommendations.
Vitamin D2 Vs. D3
You may notice vitamin D supplements are often classified in one of two forms:
Vitamin D2 is commonly referred to as being 'plant-derived' while vitamin D3 is 'animal-derived'.
Vitamin D2 (ergocalciferol) comes from ergosterol, a sterol found in fungi and yeast. Vitamin D2 supplements are made by irradiating (i.e. using ultraviolet light) ergosterol from yeast.
Most vitamin D3 supplements are produced similarly but via ultraviolet irradiation of 7-dehydrocholesterol from lanolin, an oily/waxy substance secreted from the glands of sheep.
In regard to which type of vitamin D is 'better', they will both effectively raise your vitamin D levels. In fact, our liver converts both to the main circulating form of vitamin D, 25-hydroxycholecalciferol.
Nevertheless, vitamin D3 appears to be more readily converted and studies show that it is far more potent, especially at high doses.
One study, aptly titled 'Vitamin D(3) is more potent than vitamin D(2) in humans', found that high doses vitamin D3 are almost twice are potent as equivalent vitamin D2 doses.
Another study, published in the Archives of Internal Medicine, found that vitamin D3 was likely more effective in reducing the risk of fractures when it compared clinical trials involving supplementation with both forms at the same or similar doses.
Most medical organizations don't recommend one form over another, but some do. For example, the Osteoporosis Society of Canada recommends D3 over D2.
Vitamin D2 is plant-based, produced in supplement form by irradiating (i.e. using ultraviolet light) ergosterol from yeast. Vitamin D3 is animal-based, with the majority produced from lanolin. Vitamin D3 is thought to be more potent than vitamin D2.
Prescription Vitamin D
An important consideration regarding vitamin D supplementation is its prescription status in the United States.
Vitamin D2 is available as a prescription drug while vitamin D3 is not, it is only available over the counter.
The vast majority and insurance plans will only cover items that require a prescription, which would leave vitamin D3 as an uncovered item. Therefore, if you are looking for your insurance to cover a vitamin D product, it will likely have to be vitamin D2.
Vitamin D2 is available as a prescription product in the United States. Therefore, your insurance may cover it if it is prescribed by your doctor. Vitamin D3 is generally not covered by insurance.
Vitamin D Drug Interactions
As stated at the beginning of this article, information regarding vitamin D drug interactions is scarce and most published ones are purely theoretical, based on what we know about its metabolism in our body.
The primary proposed mechanism behind potential interactions is that vitamin D affects CYP3A4, a liver enzyme that studies report is responsible for at least the partial metabolism of over 50% of known drugs.
Inhibiting CYP3A4 will decrease the metabolism of drugs that are substrates for that enzyme. This could lead to dangerously high drug concentrations, increasing the risk of side effects.
A well-known CYP3A4 interaction is between clarithromycin and the cholesterol medication simvastatin:
- Clarithromycin inhibits CYP3A4, decreasing simvastatin metabolism. This, in turn, increases drug levels, increasing the risk of rhabdomyolysis, a condition characterized by the breakdown of muscle tissue.
Additionally, there are a few drugs that can impair vitamin D metabolism. I discuss these as well.
There are a variety of mechanisms by which vitamin D may cause drug interactions, notably, by affecting CYP3A4.
In the liver, CYP3A4 converts both vitamin D2 and vitamin D3 to 25-hydroxycholecalciferol, referred to as (25(OH)D). This is the main circulating form of vitamin D (which is then further processed in other areas of the body).
As stated, CYP3A4 is an enzyme that is largely responsible for the metabolism of many drugs.
It is theorized that vitamin D can perhaps alter the activity of CYP3A4, either by inhibiting it, or by inducing it, which means to make it more active. These effects could, in turn, affect the metabolism of other drugs.
It appears the most likely interaction with vitamin D is the induction of CYP3A4.
CYP3A4 contains a 'vitamin D response element'. CYP3A4 expression is thought to be up-regulated (made more active) in the presence of vitamin D (specifically a by-product of vitamin D metabolism, 1,25(OH)2D).
Therefore, due to the increased activity of CYP3A4 in the presence of vitamin D, drugs may be metabolized more quickly.
Vitamin D may alter the activity of the liver enzyme CYP3A4, potentially affecting the metabolism of many drugs.
Vitamin D - CYP3A4 Studies
To illustrate the effect that vitamin D levels can have on CYP3A4, one study, published in 'Drug Metabolism and Disposition', investigated whether the concentrations of certain drugs metabolized via CYP3A4 exhibited seasonal changes based on varying vitamin D levels from altered sun exposure.
As we tend to get more vitamin D in the summer months (due to exposure to sunlight), the authors of the study hypothesized that drug concentrations would decrease during this time of year if higher vitamin D concentrations do indeed 'up-regulate' (i.e. increase the activity) of CYP3A4.
The study concluded:
"Seasonal differences in UV light and the resulting impact on individual vitamin D levels may lead to seasonal changes in the activity of enzymes and transporters of major relevance for drug disposition."
So the study did indeed find a relationship between CYP3A4 activity and changes in vitamin D levels from altered sunlight exposure. Although more rigorous trials are needed to draw definitive conclusions, this is something worth investigating further.
In a similar vein, one study published in Clinical Pharmacology & Therapeutics, reported statistically significantly lower concentrations of Lipitor (atorvastatin) and its metabolites among individuals taking 800 IU vitamin D per day versus those who did not take it.
It was theorized that vitamin D supplementation increased the activity of CYP3A4, decreasing overall Lipitor metabolism.
Based on all the data available, theoretically, any drug that is metabolized via CYP3A4 (there are a lot) could have a potential interaction with vitamin D.
In total, however, published cases of significant vitamin D interactions are few and far between. The extent of CYP3A4 inhibition by vitamin D, although it seems to exist, doesn't appear to be overly strong.
It is possible that we are just not aware of potentially harmful ones, but in all likelihood, most aren't all that significant, which is hopefully a conclusion we can draw as more research is done.
Several studies report that vitamin D levels affect the expression of CYP3A4. High levels of vitamin D may increase CYP3A4 activity, increasing metabolism of certain drugs like Lipitor.
Vitamin D With Effexor
As your question was specifically regarding Effexor (venlafaxine), let's take a look at how vitamin D could interact with it.
Venlafaxine is a substrate of the metabolizing enzyme CYP2D6, which produces the active metabolite O-desmethylvenlafaxine. Data indicates that Venlafaxine is likely metabolized by CYP3A4 also, but its effect is thought to be minor.
The prescribing information for Effexor tablets states that interactions with venlafaxine in regard to CYP3A4 are likely insignificant:
"CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, Ndesmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small."
Drug databases, like DrugBank, list interactions based on published documentation of said interactions as well as based on theoretical mechanisms.
Drugbank does in fact list 'venlafaxine' as a possible 'enzyme-based' interaction with vitamin D, but this is based simply on the fact that venlafaxine is partially metabolized by CYP3A4. In all likelihood, the interaction is not significant as CYP2D6 is the predominant enzyme in venlafaxine metabolism.
The risk of an interaction between vitamin D and Effexor (venlafaxine) is low.
Drugs That Interfere With Vitamin D
Aside from drugs that interact with vitamin D, there are several that may inhibit its absorption. These drugs include:
Bile Acid Sequestrants
Once very commonly prescribed for the management of cholesterol, bile acid sequences are rarely used since Statin drugs came on the market. Bile acid sequestrants include:
These drugs, as the name suggests, bind bile acids in the gastrointestinal tract. They can also bind fat-soluble vitamins, like vitamin A and vitamin D. Therefore taking bile acid sequestrants and fat-soluble vitamins at the same time is not recommended, as they could significantly reduce the absorption of them.
Fat absorption inhibitors
Fat absorption inhibitors, such as the over the counter product Alli (orlistat), block the absorption of dietary fats. Since vitamin D is fat-soluble, orlistat may also inhibit absorption.
Other Drug - Vitamin D Concerns
Looking outside of drug interactions, there are concerns that several drugs could affect vitamin D levels in other ways.
The National Institute of Health warns of an interaction with corticosteroids, as they can impair vitamin D metabolism. This isn't likely a concern with short-term use, but chronic use may be a significant factor in bone-loss and the development of osteoporosis.
Although not impacting vitamin D directly, many medications, like hydroxychloroquine, cause you to be more sensitive to light. It may be recommended that you avoid excessive sun exposure, which of course could cause a vitamin D deficiency.
Drugs that cause changes to your electrolyte balance, specifically calcium, could affect vitamin D levels.
Thiazide diuretics, such as hydrochlorothiazide, reduce the excretion of calcium. Theoretically, in combination with vitamin D, they could put you at risk of certain conditions like hypercalcemia.
It's been extensively reported that those taking antiepileptic drugs have a far higher incidence of osteoporosis than those not on them. It has been theorized that certain ones increase the activity of CYP3A4, increasing the metabolism of vitamin D.
As more studies have been completed, it doesn't appear as though the effect these drugs have on CYP3A4 is responsible for the low levels of vitamin D. One large review study states on the matter:
"Overall, the literature suggests that the effect of AEDs on vitamin D status may only be evident among individuals with insufficient exposure to exogenous sources of vitamin D (diet, supplements or UV exposure)."
Overall, the risk of significant drug interactions with vitamin D seems to be low. Nevertheless, it is an area that requires further study based on its known effects on the metabolizing enzyme CYP3A4.
- Elsevier ClinicalKey: Ergocalciferol (subscription required) (Accessed 1/29/19)
- Elsevier ClinicalKey: Cholecalciferol (subscription required) (Accessed 1/29/19)
- Dietary Reference Intakes for Calcium and Vitamin D. PubMed
- Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. PubMed
- Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada (summary) PubMed
- Drug-vitamin D interactions: A systematic review of the literature. PubMed
- Vitamin D(3) is more potent than vitamin D(2) in humans. PubMed
- Vitamin D Fact Sheet for Health Professionals. National Institute of Health
- Vitamin D Deficiency. New England Journal of Medicine
- Transcriptional control of intestinal cytochrome P-4503A by 1alpha,25-dihydroxy vitamin D3. PubMed
- Vitamin D. American Academy of Dermatology
- Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. ScienceDirect
- CYP3A4 is a vitamin D-24- and 25-hydroxylase: analysis of structure function by site-directed mutagenesis. PubMed
- Seasonal Variation in Blood Drug Concentrations and a Potential Relationship to Vitamin D. PubMed
- Effexor Prescribing Information
- Drugbank: Cholecalciferol
- Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. PubMed
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