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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528301/?tool=EBI |
| _version_ | 1818444226699984896 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T19:12:34Z |
| format | Article |
| id | doaj.art-70d4271398e1490ea4a69f7b7d98a340 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T19:12:34Z |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-70d4271398e1490ea4a69f7b7d98a3402022-12-21T22:50:42ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-011610Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in miceKavya AnnuKazuto YasudaWilliam V. CaufieldBurgess B. FreemanErin G. SchuetzVitamin 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.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528301/?tool=EBI |
| spellingShingle | 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 PLoS ONE |
| title | 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_short | 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 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528301/?tool=EBI |
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