Vitamin D and Sunlight Influence Effects of Medication

Summary
A drug or chemical is usually broken down and used by the body with the help of some mediators called enzymes. One of the most common enzymes is the CYP3A4. Studies have shown that vitamin D levels, which are related to the amount of exposure to sun, may affect the production of this enzyme. The current study was conducted to see if changes in exposure to sunlight, caused by seasonal changes, affected the metabolism of some immunity-suppressing drugs that use the CYP3A4 enzyme. The results showed that of the four drugs tested, sirolimus and tacrolimus showed more metabolism in summers (between July and September), as compared to winters (between January and March). This was especially so in countries that are situated closer to the Arctic. The metabolism of the other two drugs, mycophenolic acid and cyclosporine, were unaffected by the seasons.

Introduction
Enzymes like CYP3A4, present in the liver, are known to be the most common mediators helping in the metabolism, utilization and ultimately, therapeutic efficacy of a drug. Earlier research has shown that factors affecting the production of these enzymes may affect the metabolism of a drug. If there is a greater rate of metabolism of the drug, the blood levels fall and the therapeutic efficacy decreases. The opposite happens with a lower rate of metabolism. A lower rate of metabolism also means more risk of side effects. Research has shown that vitamin D affects the expression of genes that help in the manufacture of these enzymes. On the other hand, vitamin D itself is manufactured by exposure to sunlight. This study was conducted to see if changes in sunlight exposure due to seasonal changes in summers and winters, affect the metabolism of certain drugs that use CYP3A4 for metabolism.

Methodology
* The study involved a trial of four drugs that are used to suppress the immunity in patients. The four drugs were tacrolimus, sirolimus, cyclosporine and mycophenolic acid. Of these, the first three utilize CYP3A4 for metabolism, while mycophenolic acid, which was used as a negative control for this study, does not.
* Each drug concentration to dosing ratio was measured for three-month durations in summer (July to September) and in winter (January to March). The first is when Vitamin D level is at the highest and the second is when it is at the lowest.
* A total of 1,671 patients on tacrolimus, 344 patients on sirolimus, 1,555 patients on cyclosporine and 530 patients on mycophenolic acid were involved in the study.

Results/Key findings
* Results showed that both tacrolimus and sirolimus, which are metabolized by CYP3A4, are metabolized at higher rates during summer, as compared to winter. Both drugs had lower concentration-to-dose ratio in summers than in winters.
* Tacrolimus concentration was lower in summer by 5 to 7 percent, while sirolimus showed greater variability and was lower in summer by 8 to 17 percent.
* Cyclosporine and mycophenolic acid concentrations were not different during the different seasons.

Next steps/Shortcomings
The authors agree that this study did not exactly measure the variations of blood levels of vitamin D at different time periods. This could have led to assumptions that may have affected the results. Also, some of the participants might be consuming vitamin D supplementations in the diet, further skewing the results. Lack of a significant effect on cyclosporine concentrations could be due to the intravenous administration of this drug which would protect it from the effects of vitamin D in the intestinal wall and liver. The authors suggest further studies that measure blood vitamin D levels, along with the administered drug levels, for better correlation.

Conclusion
This study highlights the fact that vitamin D concentration variations due to different amounts of sun exposure may affect the metabolism, therapeutic efficacy and bioavailability of drugs to a significant extent. The authors suggest that the clinical significance of such variations might be evident for these immunity suppressing drugs because monitoring of efficacy is more stringent. However, in other diseases like heart disease and diabetes and with other drugs that are metabolized by CYP3A4 and other enzymes modified by vitamin D, the effects of seasonal changes may not be so clear because of lack of monitoring. The authors suggest further studies to explore this variation in detail and study its clinical relevance.

For More Information:
Seasonal Variation in Blood Drug Concentrations and a Potential Relationship to Vitamin D
Publication Journal: American Society for Pharmacology and Experimental Therapeutics, February 2011
By Jonatan D Lindh; Marine L Andersson; Karolinska University Hospital Huddinge, Stockholm, Sweden

*FYI Living Lab Reports Are Summaries of the Original Research.


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