Physiogenomics | Pharmacogenomics | Pharmacokinetics & Drug Delivery | Molecular Pharmacology
Intestinal CYP3A4 and midazolam disposition in vivo show seasonal variation and associate with VDR polymorphisms
Ranjit K Thirumaran*, Jatinder K Lamba, Richard B Kim, Bradley L Urquhart, Jamie C Gregor, Nilesh Chande, Yiping Fan, Kenneth E Thummel, Stephen D Hall, Erin G Schuetz
*Corresponding author: Ranjit K Thirumaran
Pharmaceutical Sciences, St.Jude Children's Research Hospital, Memphis, TN, USA
F1000Posters 2012, 3: 256 (poster) [English]
17th North American Regional International Society for the Study of Xenobiotics Meeting 2011, 16 - 20 Oct 2011, A12
Vitamin D, whose levels vary seasonally with UV sunlight, binds the vitamin D receptor (VDR) and transcriptionally regulates intestinal CYP3A4 expression. We tested the hypothesis that intestinal CYP3A4 expression and midazolam disposition in vivo varies seasonally, and is associated with VDR genotype.
Genetic variations in VDR, a direct transcriptional activator of intestinal CYP3A4, are associated with CYP3A4 duodenal and jejunal expression.
CYP3A4 intestinal expression was higher, and midazolam oral clearance was faster in the spring/summer compared with fall/winter months, a finding most likely related to annual changes in UV sunlight and vitamin D levels.
Our results add to our growing understanding of the interindividual differences in first pass intestinal extraction efficiency following oral administration of CYP3A4 substrates.
Our results support further testing for how seasonal, regional, racial and ethnic differences in vitamin D levels correlate with CYP3A4 mediated drug clearance.
Comprehensive testing for VDR genotype/UV sunlight-vitamin D levels requires inclusion of larger populations, as well as more comprehensive, standardized, and precise approaches to capturing environmental information.
Copyrights: Seasonal Levels of UV Sunlight Figure 1 was reproduced with kind permission from: Hicke JA et al (2008) J Geophys Res 113, D21302
Seasonal Levels of UV Sunlight Figure 2 was reproduced with kind permission from: Tarasick DW et al (2003) Atmosphere Ocean 41(2), 121-138
No relevant competing interests disclosed.
National Institutes of Health (NIH), NIGMS R01GM094418
National Institutes of Health (NIH), NIGMS PGRN U01GM092666
National Institutes of Health (NIH), P30 CA21765
Please note that most posters on this site present work that is preliminary in nature and has not been peer reviewed.
This poster is open access subject to the CC BY-NC Creative Commons 3.0 License