The influence of ethanol on drug metabolism and disposition via carboxylesterase-mediated transesterification

Persistent Link:
http://hdl.handle.net/10150/289533
Title:
The influence of ethanol on drug metabolism and disposition via carboxylesterase-mediated transesterification
Author:
Bourland, James Alain, 1958-
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:
Carboxylesterase enzymes hydrolyze a wide variety of ester-containing xenobiotics to yield carboxylic acids. It has now been determined that these enzymes catalyze the ethanolic transesterification of ester-containing compounds. Perhaps the most widely publicized and significant transesterification reaction is the conversion of cocaine (COC) to cocaethylene (CE) in the presence of ethanol. The formed CE possesses pharmacological activity, nearly identical to COC, a longer half-life and is more toxic than COC. We hypothesized that the transesterification of COC to CE is not unique and other compounds containing carboxyl ester groups might undergo transesterification in the presence of ethanol. Both methyl-ester and ethyl-ester-containing compounds were investigated using an in vitro and in vivo paradigm. Cocaethylene (CE), meperidine (MEP) and methylphenidate (MPH) are all compounds containing carboxyl ester groups which are extensively metabolized to carboxylic acids. Excised liver from male Sprague-Dawley rats were homogenized and centrifuged at 9,000g and the S9 fraction collected. Each drug investigated was separately incubated with S9 at 37°C with and without ethanol or ²H₆-ethanol. Parent drugs and predicted ethyl-ester formation products were assayed via gas chromatography/mass spectrometry (GC/MS). The experiments were repeated in vivo in rats. Animals were dosed with drug in the absence or presence of ethanol or ²H₆-ethanol. Plasma was collected and assayed for parent drug and ethyl-ester formation products by GC/MS. Pharmacokinetic parameters were calculated for both in vitro and in vivo experiments. 2-Meperidine and 2-cocaethylene were formed from MEP and CE, respectively, in the presence of ²H₆-ethanol. The pharmacokinetics of meperidine and cocaethylene were significantly altered, increasing t1/2, when ethanol was given in combination with drug. Ethylphenidate (EPH) was formed both in vivo and in vitro when MPH and ethanol were administered. There was no significant change in MPH pharmacokinetics in the presence of ethanol both in vitro and in vivo. EPH administered to male Sprague-Dawley rats increased locomotor activity in equal intensity and duration to MPH. All ethanolic transesterification reactions investigated were completely inhibited by the addition of specific and non-specific carboxylesterase inhibitors in vitro, implicating a carboyl esterase-mediated transesterification process.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Toxicology.; Health Sciences, Pharmacology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology and Toxicology
Degree Grantor:
University of Arizona
Advisor:
Mayersohn, Michael

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleThe influence of ethanol on drug metabolism and disposition via carboxylesterase-mediated transesterificationen_US
dc.creatorBourland, James Alain, 1958-en_US
dc.contributor.authorBourland, James Alain, 1958-en_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.abstractCarboxylesterase enzymes hydrolyze a wide variety of ester-containing xenobiotics to yield carboxylic acids. It has now been determined that these enzymes catalyze the ethanolic transesterification of ester-containing compounds. Perhaps the most widely publicized and significant transesterification reaction is the conversion of cocaine (COC) to cocaethylene (CE) in the presence of ethanol. The formed CE possesses pharmacological activity, nearly identical to COC, a longer half-life and is more toxic than COC. We hypothesized that the transesterification of COC to CE is not unique and other compounds containing carboxyl ester groups might undergo transesterification in the presence of ethanol. Both methyl-ester and ethyl-ester-containing compounds were investigated using an in vitro and in vivo paradigm. Cocaethylene (CE), meperidine (MEP) and methylphenidate (MPH) are all compounds containing carboxyl ester groups which are extensively metabolized to carboxylic acids. Excised liver from male Sprague-Dawley rats were homogenized and centrifuged at 9,000g and the S9 fraction collected. Each drug investigated was separately incubated with S9 at 37°C with and without ethanol or ²H₆-ethanol. Parent drugs and predicted ethyl-ester formation products were assayed via gas chromatography/mass spectrometry (GC/MS). The experiments were repeated in vivo in rats. Animals were dosed with drug in the absence or presence of ethanol or ²H₆-ethanol. Plasma was collected and assayed for parent drug and ethyl-ester formation products by GC/MS. Pharmacokinetic parameters were calculated for both in vitro and in vivo experiments. 2-Meperidine and 2-cocaethylene were formed from MEP and CE, respectively, in the presence of ²H₆-ethanol. The pharmacokinetics of meperidine and cocaethylene were significantly altered, increasing t1/2, when ethanol was given in combination with drug. Ethylphenidate (EPH) was formed both in vivo and in vitro when MPH and ethanol were administered. There was no significant change in MPH pharmacokinetics in the presence of ethanol both in vitro and in vivo. EPH administered to male Sprague-Dawley rats increased locomotor activity in equal intensity and duration to MPH. All ethanolic transesterification reactions investigated were completely inhibited by the addition of specific and non-specific carboxylesterase inhibitors in vitro, implicating a carboyl esterase-mediated transesterification process.en_US
dc.description.noteDigitization note: p.184 missing from paper original.-
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Toxicology.en_US
dc.subjectHealth Sciences, Pharmacology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMayersohn, Michaelen_US
dc.identifier.proquest9738952en_US
dc.identifier.bibrecord.b37468078en_US
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