Seasonal Variation in Blood Drug Concentrations and a Potential Relationship to Vitamin D

Abstract

ABSTRACT:The most important enzyme in hepatic drug metabolism is cytochrome P450 3A4. Published in vitro data indicate that vitamin D may up-regulate the expression of the CYP3A4 gene. Individual vitamin D levels are highly dependent on sunlight exposure and show great seasonal variability in northern countries. The aim of the present study was to investigate whether plasma concentrations of CYP3A4 drug substrates exhibit seasonal changes compatible with a stimulatory effect of vitamin D on drug metabolism. Three immunosuppressants (tacrolimus, sirolimus, and cyclosporine) were analyzed, because these CYP3A4 drug substrates are subject to long-term use and repeated concentration determinations. In addition, mycophenolic acid was included in the analysis as a control drug independent of CYP3A4 metabolism. Concentration-to-dose ratios were extracted from the Karolinska Therapeutic Drug Monitoring database and compared between the 3-month periods of lowest and highest vitamin D levels. Sirolimus and tacrolimus levels showed seasonal variability that was highly consistent with changes in vitamin D; for example, significantly lower drug concentrations in July to September than in January to March. As expected, no significant difference was evident for mycophenolic acid, but this result was also the case with cyclosporine, possibly due to cross-reactivity of CYP3A4-mediated metabolites with the immunoassay used for quantification. In conclusion, there is cyclic variation in blood levels of important immunosuppressants throughout the year that correlates with UV light-dependent changes in vitamin D levels. Even though a causal relationship remains to be established, it is suggested that individual differences in vitamin D may contribute to variability in drug metabolism and disposition.

Serum Levels of 25-Hydroxyvitamin D and the CYP3A Biomarker 4β-Hydroxycholesterol in a High-Dose Vitamin D Supplementation Study

“…Taken together, we hypothesized that CYP3A4 expression and the corresponding drug-metabolizing capacity might display cyclic changes over the different seasons. Indeed, in a retrospective study on a large patient material from therapeutic drug monitoring, we were able to show such cyclic, seasonal variability in blood levels of the important immunosuppressants tacrolimus and sirolimus, known to be metabolized by CYP3A4 (Lindh et al, 2011). Significantly lower concentration-to-dose ratios were evident during the months of peak vitamin D levels, July-September, compared with December through February (Lindh et al, 2011).…”

“…Indeed, in a retrospective study on a large patient material from therapeutic drug monitoring, we were able to show such cyclic, seasonal variability in blood levels of the important immunosuppressants tacrolimus and sirolimus, known to be metabolized by CYP3A4 (Lindh et al, 2011). Significantly lower concentration-to-dose ratios were evident during the months of peak vitamin D levels, July-September, compared with December through February (Lindh et al, 2011). This original finding raised several important questions, for example whether the individual vitamin D status is predictive of CYP3A4 activity and if treatment of patients with vitamin D results in higher CYP3A4-dependent drug metabolism.…”

“…Although the width of the confidence interval was such that a weak correlation (r # 0.3) cannot be ruled out, this suggests that individual vitamin D level in serum is not an important predictor of hepatic drug metabolism of CYP3A4 substrates. It remains to be understood if the previously observed seasonal variability in blood levels of CYP3A4 drugs substrates (Lindh et al, 2011) primarily reflects variability in intestinal first-pass metabolism of orally administered drugs. An important observation in the present study, however, was the negative relationship between individual CRP levels and the CYP3A4 biomarker 4b-hydroxycholesterol, which supports previous data that acute and/or chronic inflammation can suppress cytochrome P450 gene expression in patients.…”

A Systematic Review about an Advance in Cyclosporine Monitoring in Kidney Transplant Recipients

“…Although CYP3A5*3 difference is in some different degree, and influence on C0 and CsA daily dosing, it seems genetic variation has little effect on the acute rejection rate in kidney transplant recipient (95). Environmental combined genetically factors also play an important role; literatures have shown that vitamin D may up-regulate the expression of the CYP3A4 gene and patient vitamin D low levels is highly in need of on sunlight and show excessive geographical and seasonal inconsistency (93). It revealed that sensitivity to CsA has inter-individual difference, and is higher in transplant recipients than in normal controls.…”

“…Also, CsA metabolites and their different organ delivery may possibly be another reasons (92). Additionally, enzymes are responsible; the most important enzyme in CsA hepatic metabolism is cytochrome P450 3A4 (93). It showed that a CsA level is mainly influenced by CYP3A4, CYP3A5 and MDR-1 genes.…”