Differential regulation of intestinal and hepatic CYP3A by 1 alpha,25-dihydroxyvitamin D-3: Effects on in vivo oral absorption and disposition of buspirone in rats
- Authors
- Maeng, Han-Joo; Trang Nguyen Kieu Doan; Yoon, In-Soo
- Issue Date
- May-2019
- Publisher
- WILEY
- Keywords
- 1,25(OH)(2)D-3; buspirone; CYP3A; testosterone; vitamin D receptor
- Citation
- DRUG DEVELOPMENT RESEARCH, v.80, no.3, pp.333 - 342
- Journal Title
- DRUG DEVELOPMENT RESEARCH
- Volume
- 80
- Number
- 3
- Start Page
- 333
- End Page
- 342
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/1527
- DOI
- 10.1002/ddr.21505
- ISSN
- 0272-4391
- Abstract
- 1 alpha,25-Dihydroxyvitamin D-3 (also called 1,25(OH)(2)D-3 or calcitriol) is the biologically active form of vitamin D, which functions as a ligand to the vitamin D receptor (VDR). It was previously reported that intestinal cytochrome P450 3A (CYP3A) expression was altered by 1,25(OH)(2)D-3-mediated VDR activation. However, to clarify whether the change in CYP3A subfamily expression by VDR activation can affect metabolic function, further evidence is needed to prove the effect of 1,25(OH)(2)D-3 treatment on CYP3A-mediated drug metabolism and pharmacokinetics. Here, we report the effects of 1,25(OH)(2)D-3 on CYP3A activity and in vivo pharmacokinetics of buspirone in Sprague-Dawley rats. CYP3A mRNA expression and CYP3A-mediated testosterone metabolism were enhanced in the intestine but were unaffected in the livers of rats treated with 1,25(OH)(2)D-3. Notably, the oral pharmacokinetic profile of buspirone (CYP3A substrate drug) and 6 '-hydroxybuspirone (major active metabolite of buspirone formed via CYP3A-mediated metabolism) was significantly altered, while its intravenous pharmacokinetic profile was not affected by 1,25(OH)(2)D-3 treatment. To the best of our knowledge, this study provides the first reported data regarding the effects of 1,25(OH)(2)D-3 treatment on the in vivo pharmacokinetics of intravenous and oral buspirone in rats, by the differential modulation of hepatic and intestinal CYP3A activity. Our present results could lead to further studies in clinically significant CYP3A-mediated drug-nutrient interactions with 1,25(OH)(2)D-3, including 1,25(OH)(2)D-3-buspirone interaction.Preclinical Research & Development
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