Walter Jessen Phd
A recent study published in the journal Drug Metabolism & Disposition offers a new model to explain individual differences in the effects of drugs and how the environment can influence the body’s ability to break them down. Researchers at the
Karolinska Institutet in Sweden have shown that the body’s ability to metabolize medicines may be closely related to sunlight exposure and vitamin D, and thus may vary with the seasons.
The principal enzymes involved in drug metabolism are the cytochrome P450 enzymes (abbreviated as CYP). The primary CYP expressed in adult human liver is cytochrome P450, subfamily IIIA, polypeptide 4 (gene name: CYP3A4). It is continuously expressed as well as activated by a variety of drugs used in the clinic. Although the reasons are unknown, CYP3A4 enzyme activity can have significant variability between different people as well as within the same person at different times.
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 use them for long periods of time, requiring repeated concentration determinations.
Researchers reviewed almost 70,000 analyses from patients who had undergone regular monitoring of the levels of tacrolimus, sirolimus or cyclosporine in their blood. The investigators found that samples collected during the late summer months of July – September had significantly lower dose-corrected concentrations of tacrolimus and sirolimus compared to those collected during winter months of January – March. In contrast, no change was detected in cyclosporine concentrations.
A more detailed analysis found that the concentrations of tacrolimus and sirolimus changed throughout the year. In the body, vitamin D formation depends on sunlight. Scientists found that the pattern of drug concentration changes closely reflected changes in the level of vitamin D in the body. In patients taking part in the study, the highest levels of vitamin D were reached when the levels of the drugs were lowest.
The results of this study are correlative. Researchers have yet to establish a causal link between sunlight exposure and the body’s ability to metabolize medicines. Nonetheless, scientists think the connection between sunlight exposure and the bioavailability of sirolimus and tacrolimus arises from activation of the liver detoxification system by vitamin D through CYP3A4.
Genetic variation has long been thought to be responsible for the differences between people to metabolize drugs. The results of this study suggest that it may be even more complicated than genetics alone.
