Pharmacokinectic and pharmacodynamic aspects of cocaine and its interaction with ethanol

Persistent Link:
http://hdl.handle.net/10150/289511
Title:
Pharmacokinectic and pharmacodynamic aspects of cocaine and its interaction with ethanol
Author:
Kim, Shinja Rhea
Issue Date:
1997
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
The main purpose of the research described in this dissertation was to evaluate various aspects of cocaine in pharmacokinetics and pharmacodynamics including: physiologically based-pharmacokinetics modeling; the influence of ethanol on cocaine disposition. Further, cocaine and cocaethylene (CE) were compared using pharmacokinetic-pharmacodynamic (PK-PD) models. Lastly, PK-PD models after cocaine and a combination of cocaine and ethanol dose were developed. Cocaine was administered by iv with or without ethanol in rats. CE was formed only in the group of rats given cocaine in the presence of ethanol. The extent of benzoylecgonine formation from cocaine significantly suppressed in the presence of ethanol. There were no statistical differences in cocaine disposition kinetics following iv cocaine dose in the presence or absence of ethanol. The PB-PK model was developed to describe cocaine disposition in the rat, dog, monkey and ultimately for scaling to humans using information developed in animals. The model gave a good prediction of tissue concentration-time profiles in animals. The prediction of the plasma concentration-time data in humans was poor when using the same tissue-to-blood-partition coefficients (R) obtained in rats. However, an excellent prediction was obtained after R was adjusted for differences in the apparent volume of distribution at steady state (rat vs. humans). The PK-PD model for cocaine or CE was developed by analyzing literature data. CE appears to be less potent in producing euphorigenic effects and equipotent to cocaine in producing physiological effects (e.g., cardiovascular function). The sigmoid Emax model was selected to describe the relationship between the physiological and euphorigenic effects produced by cocaine, ethanol and CE and their respective concentrations in the effect compartment. This model gave a good prediction for those effects. It appears that increased heart rate and "cocaine high" after a combination dose of cocaine and ethanol compared to cocaine alone was due to both the increase in cocaine concentration and the CE formed following ethanol exposure. Similarly, increased effect of "any high" or "good effect" after a combined dose appears to be due to cocaine (in the presence of ethanol), ethanol and CE formed in the presence of cocaine and ethanol.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Pharmacology.; Chemistry, Pharmaceutical.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacy Practice and Sciences
Degree Grantor:
University of Arizona
Advisor:
Mayersohn, Michael

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titlePharmacokinectic and pharmacodynamic aspects of cocaine and its interaction with ethanolen_US
dc.creatorKim, Shinja Rheaen_US
dc.contributor.authorKim, Shinja Rheaen_US
dc.date.issued1997en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractThe main purpose of the research described in this dissertation was to evaluate various aspects of cocaine in pharmacokinetics and pharmacodynamics including: physiologically based-pharmacokinetics modeling; the influence of ethanol on cocaine disposition. Further, cocaine and cocaethylene (CE) were compared using pharmacokinetic-pharmacodynamic (PK-PD) models. Lastly, PK-PD models after cocaine and a combination of cocaine and ethanol dose were developed. Cocaine was administered by iv with or without ethanol in rats. CE was formed only in the group of rats given cocaine in the presence of ethanol. The extent of benzoylecgonine formation from cocaine significantly suppressed in the presence of ethanol. There were no statistical differences in cocaine disposition kinetics following iv cocaine dose in the presence or absence of ethanol. The PB-PK model was developed to describe cocaine disposition in the rat, dog, monkey and ultimately for scaling to humans using information developed in animals. The model gave a good prediction of tissue concentration-time profiles in animals. The prediction of the plasma concentration-time data in humans was poor when using the same tissue-to-blood-partition coefficients (R) obtained in rats. However, an excellent prediction was obtained after R was adjusted for differences in the apparent volume of distribution at steady state (rat vs. humans). The PK-PD model for cocaine or CE was developed by analyzing literature data. CE appears to be less potent in producing euphorigenic effects and equipotent to cocaine in producing physiological effects (e.g., cardiovascular function). The sigmoid Emax model was selected to describe the relationship between the physiological and euphorigenic effects produced by cocaine, ethanol and CE and their respective concentrations in the effect compartment. This model gave a good prediction for those effects. It appears that increased heart rate and "cocaine high" after a combination dose of cocaine and ethanol compared to cocaine alone was due to both the increase in cocaine concentration and the CE formed following ethanol exposure. Similarly, increased effect of "any high" or "good effect" after a combined dose appears to be due to cocaine (in the presence of ethanol), ethanol and CE formed in the presence of cocaine and ethanol.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Pharmacology.en_US
dc.subjectChemistry, Pharmaceutical.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacy Practice and Sciencesen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMayersohn, Michaelen_US
dc.identifier.proquest9738944en_US
dc.identifier.bibrecord.b37460225en_US
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