Birabaharan, Jonathan
(2024)
Translational Insights into the Pharmacokinetics of Morphine and M3G in Traumatic Brain Injury: Understanding the Implications for Secondary Injury.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
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Abstract
Traumatic Brain Injury (TBI) is the leading cause of death and disability in both children and adults aged 1 to 44. Despite promising preclinical indications, effective treatments often falter in clinical trials, highlighting the urgent need to understand how pharmacokinetics translate from preclinical models to clinical settings, along with their influence on pharmacodynamics. This translational gap hinders effective interventions in TBI research.
This dissertation aims to bridge this gap by developing methodologies to assess pharmacokinetic changes in TBI. This dissertation specifically focuses on morphine, a commonly administered sedative, and its major metabolite, morphine-3-glucuronide (M3G). Both these analytes, either directly or indirectly, have been linked to increased inflammation and neurotransmitter dysregulation in previous in vitro and rodent studies. By understanding how TBI alters morphine's pharmacokinetics and its impact on secondary injury pathways, this research seeks to enhance treatment outcomes for TBI patients.
Initially, an ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) assay was developed to measure sedatives in critical care populations. This method enables simultaneous quantification of nine analytes, including midazolam, dexmedetomidine, morphine, hydromorphone, fentanyl and their metabolites, requiring minimal sample preparation and only 10 minutes for analysis with 100μL of plasma.
Furthermore, the assay was utilized in a clinical study involving 71 pediatric critical care patients receiving mechanical ventilation. The assay successfully measured 91% of 364 samples within their quantifiable range. Population pharmacokinetic models for midazolam and morphine were created, with clearance estimates aligning closely with literature values. However, evaluating the effect of TBI alone was challenging due to recruiting patients and the variability from concurrent injuries.
Additionally, pharmacokinetics of morphine and M3G post-TBI were investigated using a rat controlled cortical impact (CCI) model to study the effect isolated from other concurrent injuries. The study revealed with morphine administration post injury, there was increased M3G exposure in plasma and brain tissue, and a potential trend with M3G formed from morphine AUC correlating with GFAP expression in the ipsilateral hippocampus.
Moreover, neurotransmitter dynamics during the subacute phase of severe TBI were explored using a rodent LFPI model. Microdialysis revealed elevated baseline glutamate levels and reduced changes during synaptic stimulation post-injury, while GABA levels remained unchanged between injured and sham animals. This characterization was essential to first understand before evaluating changes of neurotransmitters when morphine and M3G are present.
Ultimately, this research aims to elucidate pharmacokinetic changes induced by TBI, particularly with morphine administration, to advance towards more effective interventions for TBI patients. By bridging the translational gap between preclinical evidence and clinical application, this dissertation strives to offer hope for improved outcomes in managing this debilitating condition.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
25 April 2024 |
| Date Type: |
Publication |
| Defense Date: |
11 March 2024 |
| Approval Date: |
25 April 2024 |
| Submission Date: |
19 April 2024 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
193 |
| 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: |
TBI, morphine, pharmacokinetics, neuroinflammation, glutamate, GABA, translation |
| Date Deposited: |
25 Apr 2024 16:02 |
| Last Modified: |
25 Apr 2024 16:02 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46190 |
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