Ji, Beihong
(2019)
Pharmacokinetics Modeling and Molecular Modeling of Drug-Drug Interactions Between Opioids and Benzodiazepines.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
The potential drug-drug interactions (DDIs) of concurrent use of opioids and benzodiazepines have aroused high attention in the world for the severe side effects when two types of drugs are co-administered. However, there is much unknown in the DDI between these two kinds of drugs. The objective of this project is to find out the mechanism underlying the DDIs between opioids and benzodiazepines. There are two basic factors can contribute to the interactions, pharmacokinetic (PK) interaction and pharmacodynamic (PD) interaction. PK interaction is one of the most common reasons that lead to DDI. This kind of interaction may occur when two drugs are metabolized by the same Cytochrome P450 enzymes. In this work, we quantitatively predicted the DDI between oxycodone and diazepam through empirical PK modeling, minimal physiologically-based PK (PBPK) modeling and full PBPK modeling. Another possibility causing the DDI is PD interaction. In PD study, we used molecular modeling techniques including molecular docking, molecular dynamics simulations and MM/PBSA calculations to predict the pharmacodynamic interaction between opioids and benzodiazepines. The results of PK interaction study indicated that benzodiazepines have limited inhibitory effect on opioids and the extent of inhibition slightly increased with the overdose of benzodiazepines. Usually PK interactions might only be observed when highly increasing the dosage of benzodiazepines. The results of PD interaction study indicated that benzodiazepines may act as agonists or antagonists of the µ- and k-opioid receptors. We concluded that PD interaction is likely to play a more important role in DDIs between opioids and benzodiazepines.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
18 April 2019 |
| Date Type: |
Publication |
| Defense Date: |
2 April 2019 |
| Approval Date: |
18 April 2019 |
| Submission Date: |
15 April 2019 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
94 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
opioid, benzodiazepine, drug-drug interaction, PK, PBPK, molecular modeling |
| Date Deposited: |
18 Apr 2019 12:09 |
| Last Modified: |
18 Apr 2019 12:09 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/36274 |
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