Date of Award

11-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Molecular and Systems Pharmacology

Research Advisor

Erin G. Schuetz, PhD

Committee

Taosheng Chen, PhD, PMP Elizabeth A. Fitzpatrick, PhD Santosh Kumar, PhD Alex Sparreboom, PhD

Keywords

Acute lymphoblastic leukemia, CXCL12, CYP3A, Dasatinib, Dexamethasone, Vitamin D deficiency

Abstract

It is a well-established phenomenon that dietary components containing CYP3A inducers or inhibitors if co-administered with drugs that are CYP3A4 substrates lead to marked drug-drug interactions. Because vitamin D is known to regulate intestinal CYP3A expression and gut CYP3A expression plays an important role in pre-systemic metabolism of CYP3A drugs, we determined the impact of vitamin D (VD3) status on systemic exposure and efficacy of chemotherapeutic agents that are CYP3A substrates. We employed VD3 sufficient and deficient mice to perform pharmacokinetics (PK) and anti-leukemic efficacy studies.

First, using hCYP3A4 transgenic mouse model we evaluated the intestinal, hepatic and renal expression of hCYP3A4, mouse CYPs and transporters in VD3 sufficient vs. deficient mice. We observed that female VD3 deficient mice had significantly lower duodenal mouse Cyp3a11 and hCYP3A4 expression than VD3 sufficient mice. Since intestinal CYP3A plays a significant role in first pass metabolism of drugs that are administered orally, chemotherapeutic agents such as dexamethasone (DEX) and dasatinib which are given orally to the patients were chosen to study the effect of VD3 status on systemic exposure of these CYP3A4 substrates.

In C57BL/6 mice, we performed dexamethasone PK study, where we observed male VD3 deficient mice had higher plasma DEX levels compared to sufficient mice on day 3.5. No significant differences were observed in females.

Another CYP3A4 substrate, dasatinib PK was also performed where AUC’s were not significantly different between groups. However, during early absorption at t = 0.25 hr, VD3 deficient male mice had significantly higher dasatinib plasma levels compared to VD3 sufficient mice. In conclusion, VD3 levels (sufficient vs. deficient) significantly altered intestinal Cyp3a expression in female hCYP3A4 mice, and in male’s, plasma exposure was different for orally administered DEX at 3.5 days, dasatinib at 0.25 hr. Ultimately, there was no significant effect of VD3 status on DEX or dasatinib PK indicating no potential vitamin drug interactions. However, DEX being a potential CYP3A inducer, we also observed significant induction of multiple mouse Cyp3a’s in intestine of VD3 deficient but not VD3 sufficient mice. This differential induction of Cyp3a’s due to vitamin D status could lead to drug interactions with other co-administered CYP3A substrates.

Given the high prevalence of VD3 deficiency in acute lymphoblastic leukemia (ALL) patients, we evaluated the effect of vitamin D deficiency on survival outcome from pre-B cell Arf -/- BCR-ABL acute lymphoblastic leukemia in a murine model. Vitamin D sufficient mice died earlier (p

To investigate the mechanism by which vitamin D affected the survival and disease growth in VD3 sufficient mice, we performed in vitro studies and demonstrated 1, 25-dihydroxy vitamin D (1, 25-(OH)2VD3) increased the number of BCR-ABL ALL cells only when co-cultured with bone marrow stroma. 1, 25-(OH)2VD3 induced CXCL12 production in vivo and in vitro in bone marrow stromal cells and CXCL12 increased stromal migration and the number of BCR-ABL blasts. Vitamin D together with ALL reprogrammed the marrow environment by increasing production of Type I and V collagens, potentially trapping ALL blasts and CXCL12 expression to support tumor progression and leukemia cell homing.

In conclusion, although vitamin D deficiency did not cause significant interactions with anti-leukemic CYP3A4 substrates, there was a significant effect on disease progression and survival of mice from BCR-ABL ALL.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

https://orcid.org/0000-0001-7312-2947

DOI

10.21007/etd.cghs.2020.0523

Additional Files
2020-031-Annu-DOA.pdf (364 kB)
Declaration of Authorship
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