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Genetic variation has been though to be responsible for the differences between people to metabolize certain drugs. The results of a recent study from the Karolinska Institutet in Sweden suggest that it may be even more complicated. Swedish reserchers have found that the body’s ability to break down medicines may be closely related to sunlight exposure and vitamin D, and thus may vary with the seasons. The study, published in the journal Drug Metabolism & Disposition, offers a completely new model to explain individual differences in the effects of drugs .
The cytochrome P450 enzyme superfamily (abbreviated as CYP) are the major enzymes involved in drug metabolism and bioactivation. Cytochrome P450, subfamily IIIA, polypeptide 4 (CYP3A4) is the primary CYP expressed in adult human liver. It is both continuously expressed as well as activated by a variety of clinically used drugs. CYP3A4 activity is known to show a significant variability not only between different people but also within the same person at different times. The reason for this variability is unknown.
The goal of the present study was to test the hypothesis that plasma concentrations of three immunosuppressant drugs — tacrolimus, sirolimus and cyclosporine — show seasonal variations associated with increased CYP34A4 enzyme via vitamin D. These drugs were used because they are dependent on the CYP3A4 metabolic pathway and most patients taking these drugs use them for long periods of time and require repeated concentration determinations.
The researchers reviewed almost 70,000 analyses from patients who had undergone regular monitoring of the levels of drugs in their blood. They found that samples collected during the summer (July-September) had significantly lower dose-corrected concentrations of tacrolimus and sirolimus compared to those collected during the winter (January – March). In contrast, no change was detected in cyclosporine concentrations.
A more detailed analysis found that the concentrations of tacrolimus and sirolimus vary throughout the year, closely reflecting the changes in the level of vitamin D in the body. The body depends on sunlight to form vitamin D. The highest levels of vitamin D in patients taking part in the study were reached when the levels of the drugs were lowest.
Although the results are correlative, not causal, scientists think the connection between sunlight, vitamin D and the bioavailability of sirolimus and tacrolimus arises from the activation by vitamin D of the liver detoxification system, specifically by increasing the amount CYP3A4. In turn, CYP3A4 is responsible for the breakdown of tacrolimus and sirolimus.
Jonatan Lindh at the Karolinska Institutet Department of Laboratory Medicine and lead author of the study said :
If the breakdown capacity increases, then higher doses of a drug are normally required in order to achieve the same effect. More research will be needed to confirm the results, but CYP3A4 is considered to be the most important enzyme in drug turnover in the body, and the results may have significance for many drugs.
Just three years ago, we reported on the International Serious Adverse Events Consortium (SAEC), which announced plans to identify genetic markers that predicted drug-related serious adverse events. The results of the current study suggest that individual differences in the effects of drugs is even more intricate than just genetics alone.
- Lindh et al. Seasonal variation in blood drug concentrations and a potential relationship to vitamin d. Drug Metab Dispos. 2011 May;39(5):933-7. Epub 2011 Feb 24.
- Sunlight can influence the breakdown of medicines in the body. Karolinska Institutet. 2011 Mar 9.