DOI

10.17077/etd.xkpwwbg8

Document Type

Dissertation

Date of Degree

Spring 2017

Access Restrictions

Access restricted until 07/13/2019

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmaceutical Sciences and Experimental Therapeutics

First Advisor

Maureen D. Donovan

Second Advisor

Laura L. Ponto

First Committee Member

Douglas R. Flanagan

Second Committee Member

Gary Milavetz

Third Committee Member

Guohua An

Abstract

The medical use of marijuana is increasing, yet little is known about the exposure-response relationships resulting in its psychoactive effects. Δ9-tetrahydrocannabinol (THC) and its active metabolite (11-hydroxy-THC; THC-OH) are the principal psychoactive components in marijuana. It is well known that the plasma concentrations of the psychoactive components of marijuana do not directly relate to the observed psychoactive effects. The presence of a counter-clockwise hysteresis in the plasma concentrations-effect plot demonstrates a temporal delay between the plasma concentrations and observed effect following the intravenous administration of THC. The overarching objective of this research was to better understand the relationship between the plasma and brain concentrations of the psychoactive components (THC and THC-OH) and the observable psychoactive effects after intravenous administration of THC, utilizing model-based approaches. Specifically, the pharmacokinetics were explored using population pharmacokinetic (Pop PK) and physiologically-based pharmacokinetic (PBPK) modeling whereas the pharmacodynamics (PD) of the psychoactive effect (“highness”) were explored using effect-compartment modeling and linking the PD to the PBPK-derived concentrations predicted in the brain and an assumed effect-site.

A “hypothetical” effect compartment model was developed to characterize the observed delay in peak “highness” ratings. A direct relationship was established between the reported psychoactive effects (“highness” or intoxication) and the predicted effect-site concentrations of both components (THC and THC-OH) using this effect-compartment modeling approach. The faster plasma to effect compartment equilibration for THC-OH indicated a more rapid equilibration of the active metabolite between plasma and the effect-site (biophase) than for the parent THC. In addition, a PBPK modeling approach was pursued to predict and relate the brain concentrations of THC and THC-OH to the psychoactive effect. The relationship between the effect and the predicted unbound brain concentration of THC indicated an indirect relationship, suggesting a temporal delay between brain concentrations of THC and observed effect. However, a direct relationship was observed between the observed effect and the unbound brain THC-OH concentrations. In addition, the unbound concentrations of THC-OH in the brain were predicted to be higher than the corresponding THC concentrations. These findings highlight the importance for the inclusion of THC-OH, in addition to THC, when relating the observed effect to the concentrations of the psychoactive components of marijuana.

These models contribute to the understanding of the PK-PD relationships associated with marijuana use and are important steps in the prediction of the pharmacodynamic effects related to the psychoactive components in marijuana and establish an approach for investigating other THC-related effects.

Public Abstract

Currently, marijuana is one of the most abused drugs throughout the world, and it is the most commonly used illicit drug in United States. The increasing interest in the use of “medical marijuana” and the movement toward legalization of the recreational use of marijuana create an increased need to better understand the relationship between the psychoactive effect and the plasma concentrations of the psychoactive components of marijuana. Delta-9-tetrahydrocannabinol (THC), the main psychoactive substance in marijuana, has prominent effects on a number of organ systems including the cardiovascular system and the brain. In addition, the active metabolite of THC, 11-hydroxy-THC (THC-OH), has also been reported to be psychoactive. Pharmacokinetics (PK) is the study of the time course of absorption, distribution, metabolism, and excretion of a drug often measured from the blood, while pharmacodynamics (PD) is the study of the relationship between the concentration of drug at the site of action (biophase compartment) and the exerted effect. The overarching objective of this research was to study the pharmacokinetics and pharmacodynamics of THC and its active metabolite from the intravenous dosing of THC.

With the advancement in computing technology and its application in the fields of clinical pharmacology and clinical pharmacokinetics, computer-based modeling and simulations have evolved as a tool for the prediction of the effects of drugs in physiological systems. In addition to the advantages of being less expensive and less labor intensive compared to animal experiments or trials on human subjects, simulations can provide information that is experimentally difficult to obtain.

The plasma concentrations of THC and THC-OH were related to the psychoactive effect using a mathematical model. The faster equilibration of metabolite from plasma-to-“hypothetical” effect site, compared to that for parent drug, was predicted. In addition, the physiologically-based pharmacokinetic model predicted higher unbound brain concentrations of THC-OH compared to corresponding THC concentrations. Furthermore, a direct relationship between predicted unbound brain concentrations of THC-OH was observed, in contrast to an indirect relationship between the predicted unbound brain concentrations of THC and observed effects. The modeling results from this research have indicated that the primary metabolite, THC-OH, might be a responsible contributor, in addition to THC, towards the elicitation of psychoactive effects following marijuana administration.

Understanding the PK-PD relationships associated with marijuana is important in order to design therapeutic treatment regimens for medically-used marijuana and to establish reliable measures of intoxication for recreational use.

Keywords

11-hydroxy-tetrahydrocannabinol, Concentration-effect relationship, Effect-compartment model, Physiologically-based pharmacokinetic (PBPK) model, Population pharmacokinetics, Δ9-tetrahydrocannabinol (THC)

Pages

xxvii, 211 pages

Bibliography

Includes bibliographical references.

Copyright

Copyright © 2017 Rakesh Awasthi

Available for download on Saturday, July 13, 2019

Share

COinS