Does Vitamin D Have Drug Interactions?

Alicia asked

Are there any drug interactions with vitamin D? I am particularly concerned with Effexor (venlafaxine).

Answer

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.

Vitamin D2 Vs. D3

You may notice vitamin D supplements are often classified in one of two forms:

• Ergocalciferol, known as vitamin D2
• Cholecalciferol, known as vitamin D3

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 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.

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.

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:

• Colestipol
• Cholestyramine

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.

Steroids

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.

Photosensitizing drugs

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.

Thiazide diuretics

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.

Antiepileptic Drugs

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)."

Final Words

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.