Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.

Vitamin D3 (VD3) induces intestinal CYP3A that metabolizes orally administered anti-leukemic chemotherapeutic substrates dexamethasone (DEX) and dasatinib potentially causing a vitamin-drug interaction. To determine the impact of VD3 status on systemic exposure and efficacy of these chemotherapeutic...

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Autores principales:	Kavya Annu, Kazuto Yasuda, William V Caufield, Burgess B Freeman, Erin G Schuetz
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2b256692a0f8435c85bc1753e5748a00
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spelling	oai:doaj.org-article:2b256692a0f8435c85bc1753e5748a002021-12-02T20:16:45ZVitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.1932-620310.1371/journal.pone.0258579https://doaj.org/article/2b256692a0f8435c85bc1753e5748a002021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0258579https://doaj.org/toc/1932-6203Vitamin D3 (VD3) induces intestinal CYP3A that metabolizes orally administered anti-leukemic chemotherapeutic substrates dexamethasone (DEX) and dasatinib potentially causing a vitamin-drug interaction. To determine the impact of VD3 status on systemic exposure and efficacy of these chemotherapeutic agents, we used VD3 sufficient and deficient mice and performed pharmacokinetic and anti-leukemic efficacy studies. Female C57BL/6J and hCYP3A4 transgenic VD3 deficient mice had significantly lower duodenal (but not hepatic) mouse Cyp3a11 and hCYP3A4 expression compared to VD3 sufficient mice, while duodenal expression of Mdr1a, Bcrp and Mrp4 were significantly higher in deficient mice. When the effect of VD3 status on DEX systemic exposure was compared following a discontinuous oral DEX regimen, similar to that used to treat pediatric acute lymphoblastic leukemia patients, male VD3 deficient mice had significantly higher mean plasma DEX levels (31.7 nM) compared to sufficient mice (12.43 nM) at days 3.5 but not at any later timepoints. Following a single oral gavage of DEX, there was a statistically, but not practically, significant decrease in DEX systemic exposure in VD3 deficient vs. sufficient mice. While VD3 status had no effect on oral dasatinib's area under the plasma drug concentration-time curve, VD3 deficient male mice had significantly higher dasatinib plasma levels at t = 0.25 hr. Dexamethasone was unable to reverse the poorer survival of VD3 sufficient vs. deficient mice to BCR-ABL leukemia. In conclusion, although VD3 levels significantly altered intestinal mouse Cyp3a in female mice, DEX plasma exposure was only transiently different for orally administered DEX and dasatinib in male mice. Likewise, the small effect size of VD3 deficiency on single oral dose DEX clearance suggests that the clinical significance of VD3 levels on DEX systemic exposure are likely to be limited.Kavya AnnuKazuto YasudaWilliam V CaufieldBurgess B FreemanErin G SchuetzPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10, p e0258579 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kavya Annu Kazuto Yasuda William V Caufield Burgess B Freeman Erin G Schuetz Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.
description	Vitamin D3 (VD3) induces intestinal CYP3A that metabolizes orally administered anti-leukemic chemotherapeutic substrates dexamethasone (DEX) and dasatinib potentially causing a vitamin-drug interaction. To determine the impact of VD3 status on systemic exposure and efficacy of these chemotherapeutic agents, we used VD3 sufficient and deficient mice and performed pharmacokinetic and anti-leukemic efficacy studies. Female C57BL/6J and hCYP3A4 transgenic VD3 deficient mice had significantly lower duodenal (but not hepatic) mouse Cyp3a11 and hCYP3A4 expression compared to VD3 sufficient mice, while duodenal expression of Mdr1a, Bcrp and Mrp4 were significantly higher in deficient mice. When the effect of VD3 status on DEX systemic exposure was compared following a discontinuous oral DEX regimen, similar to that used to treat pediatric acute lymphoblastic leukemia patients, male VD3 deficient mice had significantly higher mean plasma DEX levels (31.7 nM) compared to sufficient mice (12.43 nM) at days 3.5 but not at any later timepoints. Following a single oral gavage of DEX, there was a statistically, but not practically, significant decrease in DEX systemic exposure in VD3 deficient vs. sufficient mice. While VD3 status had no effect on oral dasatinib's area under the plasma drug concentration-time curve, VD3 deficient male mice had significantly higher dasatinib plasma levels at t = 0.25 hr. Dexamethasone was unable to reverse the poorer survival of VD3 sufficient vs. deficient mice to BCR-ABL leukemia. In conclusion, although VD3 levels significantly altered intestinal mouse Cyp3a in female mice, DEX plasma exposure was only transiently different for orally administered DEX and dasatinib in male mice. Likewise, the small effect size of VD3 deficiency on single oral dose DEX clearance suggests that the clinical significance of VD3 levels on DEX systemic exposure are likely to be limited.
format	article
author	Kavya Annu Kazuto Yasuda William V Caufield Burgess B Freeman Erin G Schuetz
author_facet	Kavya Annu Kazuto Yasuda William V Caufield Burgess B Freeman Erin G Schuetz
author_sort	Kavya Annu
title	Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.
title_short	Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.
title_full	Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.
title_fullStr	Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.
title_full_unstemmed	Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.
title_sort	vitamin d levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/2b256692a0f8435c85bc1753e5748a00
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Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.

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