Assessment of Hydrolysis of Prodrugs and Co-drugs Derived from 5-Aminolevulinic Acid and Mycophenolic Acid
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Issue Date
2023-08
Authors
Strumski, Kaitlyn '23
Degree
MS in Pharmaceutical Sciences
Advisor
Hass, Martha A.
Committee Members
Lewis, L. Michelle
Shah, Manish
Shah, Manish
Journal Title
Journal ISSN
Volume Title
Abstract
Mycophenolic acid (MPA) and 5-aminolevulenic acid (ALA) have been known to reduce the symptoms associated with autoimmune skin disease, psoriasis. It is hypothesized that the combination of these two drugs, when delivered simultaneously to the skin, will provide synergistic therapeutic benefit in suppressing the symptoms of psoriasis. This research project aims to evaluate the in vitro efficacy of prodrugs and investigational co-drugs derived from ALA and MPA using an immortalized human keratinocyte cell line (HaCaT) as models for drug behavior in human skin. Previously, it was shown that MPA and ALA do not negatively interact, but rather improve treatment when administered together. This project is specifically aimed at using HaCaT cells as a viable “skin” model to determine if the prodrugs and the investigational co-drugs derived from ALA and MPA are sufficiently metabolized to release therapeutically effective doses of the parent compounds that elevate protoporphyrin IX (PpIX) and inhibit inosine-5′-monophosphate dehydrogenase (IMPDH). HaCaT cells were grown, and cultures were treated with ALA-BE and ALA separately to evaluate the increase in PpIX which is hypothesized to correlate with hydrolysis of ALA-BE into the active compound ALA. MPA-ME was synthesized, HaCaT cell lysate was prepared, and the lysates were treated with MPA and MPA-ME. The MPA treated lysates were analyzed using HPLC to determine the extraction efficiency of MPA and the MPA-ME treated lysates were analyzed using HPLC to determine the percent hydrolysis of MPA-ME into the active compound MPA. This research establishes that HaCaT cells contain hydrolytic enzymes capable of promoting hydrolysis of ALA-/MPA- prodrugs and co-drugs that results in release of the parent drugs, ALA and MPA. The activity of the parent compounds correlates with the extent to which the prodrugs and co-drugs hydrolyze in epithelial cells.
Citation
Strumski K. Assessment of hydrolysis of prodrugs and co-drugs derived from 5-aminolevulinic acid and mycophenolic acid [thesis]. Ann Arbor (MI): Proquest LLC; 2023. 65 p.
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