Tang, Chenxiao
(2021)
Developing Novel and Optimizing Available CNS Therapies: Preclinical Development of 20-HETE Formation Inhibitors and Population Pharmacokinetics of Propofol in ICU patients.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
20-hydroxyeicosatetraenoic acid (20-HETE) is a vasoconstrictive metabolite of arachidonic acid by cytochrome P450 (CYP) 4A11 and 4F2 in humans. Inhibition of 20-HETE formation produces neuroprotective effects in cardiac arrest and stroke preclinical models. Clinical evidence shows that high CSF 20-HETE level is associated with three-fold increased mortality and unfavorable outcomes in subarachnoid hemorrhage patients. These findings suggest that 20-HETE synthase inhibition is a potential therapeutic strategy for neuroprotection after brain injury. HET0016, a 20-HETE inhibitor, did not enter clinical development due to poor solubility and short half-life. Currently, a clinically relevant 20-HETE inhibitor is not available to be evaluated as a therapeutic intervention.
The primary goal of this dissertation is to develop novel 20-HETE formation inhibitors that have strong potency and favorable physicochemical, metabolic stability, selectivity, solubility, CYP inhibition, and blood-brain barrier (BBB) permeability. We developed analytical methods to facilitate metabolic stability, CYP inhibition evaluation, and quantify the novel compound in a pharmacokinetic study. After iterations of screening and in vitro evaluation for 143 novel compounds, UPMP107 was identified as a preclinical candidate that had strong potency and advantage of highly metabolically stable, wide selectivity window, and good brain penetration in vitro. Intravenous administration of 107 to postnatal day 17 rats showed that it could penetrate BBB and reduce brain 20-HETE levels. The 20-HETE inhibitory effect was maintained up to 9 hrs after IV administration at 20 mg/kg. UPMP107 exhibited a biphasic plasma concentration-time profile after IV administration. It has a low clearance, an intermediate volume of distribution, and a relatively short half-life.
The secondary goal was to optimize marketed CNS therapy, propofol, to improve the neurological outcome. The pharmacokinetics of propofol in an ICU population was described using a population pharmacokinetic model. A two-compartment, zero-order infusion, first-order elimination model best described the profile. This model could be used to explore the relationship between propofol exposure and sedative response to optimize the therapy in the ICU population.
Collectively, the work identified a novel compound that inhibits 20-HETE formation and can be used in proof of concept animal studies. Propofol pharmacokinetics was characterized in the ICU population, and the model could potentially be used to explore an exposure-response relationship in the future.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
15 April 2021 |
| Date Type: |
Publication |
| Defense Date: |
19 March 2021 |
| Approval Date: |
15 April 2021 |
| Submission Date: |
12 April 2021 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
245 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
secondary brain injury, 20-HETE, drug development |
| Date Deposited: |
15 Apr 2021 13:27 |
| Last Modified: |
15 Apr 2021 13:27 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/40607 |
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