The Effect of Ethanol on Oral Cocaine Pharmacokinetics Reveals an Unrecognized Class of Ethanol-Mediated Drug Interactions

Parker, Robert B.; Laizure, S. Casey

doi:10.1124/dmd.109.030056

Cited by 34 publications

(20 citation statements)

References 39 publications

(50 reference statements)

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“…Indeed, Crow et al (2010) observed that ethanol is a potent inhibitor of CES2, meaning that the observed effect of ethanol could be due to inhibition of presystemic clearance mediated by hCES2 (intestine) rather than an effect on systemic clearance mainly mediated by hCES1. This hypothesis is corroborated by the observation that the terminal half-life of cocaine was not impacted by ethanol treatment (Parker and Laizure, 2010).…”

Section: Discussionsupporting

confidence: 74%

“…In addition, in vivo evidence with methylphenidate (substrate of hCES1) further confirmed our findings that transesterification can occur in the presence of ethanol and that this does not impact the clearance of the ester prodrug itself although formation of its hydrolyzed product (ritalinic acid) was impaired (Koehm et al, 2010). However, this finding (the lack of effect of ethanol on the ester prodrug clearance) is not supported by the data published on the interaction between cocaine and ethanol, which clearly highlights that ethanol inhibits the clearance of cocaine (Laizure et al, 2003;Parker and Laizure, 2010). One of the potential reasons is that cocaine is not only cleared by hCES1 but also by hCES2.…”

Section: Discussioncontrasting

confidence: 50%

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In Vitro Hydrolysis and Transesterification of CDP323, an α4β1/α4β7 Integrin Antagonist Ester Prodrug

et al. 2013

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We identified the enzyme(s) involved in the hydrolysis of the ethyl ester prodrug CDP323 (C 28 H 29 BrN 4 0 3 ) and characterized its transesterification in the presence of ethanol with special emphasis on the risks of drug-drug interaction. The hydrolysis of CDP323 was evaluated in vitro using human liver and intestinal microsomes and recombinant human carboxylesterases (hCES1 and 2) and was shown to be approximately 20-fold higher in human liver microsomes when compared with human intestinal microsomes and in hCES1 when compared with hCES2. Nonspecific inhibitors of carboxylesterases significantly inhibited the hydrolysis of CDP323 (>80% inhibition) while specific inhibitors of CES2, acetylcholine esterase, arylesterase, and butyrylcholinesterase did not impair the hydrolysis reaction. The effect of ethanol on the kinetic parameters for hydrolysis was investigated, demonstrating that at high concentration (2%), Michaelis-Menten constant (K m ), maximum velocity (V max ), and intrinsic clearance (CL int ) for the formation of the hydrolyzed product were decreased (∼40%). The use of deuterated ethanol allowed more mechanistic investigations of the transesterification mechanism and showed that the intrinsic clearance based on parent loss was not impaired in the presence of alcohol. Overall, our data demonstrate that CDP323 is mainly hydrolyzed by hCES1 and is prone to transesterification in the presence of ethanol. Transesterification mechanisms compete with hydrolysis without impairing the overall clearance of the ester prodrug. Based on in vitro results, the risk of a clinically significant drug-drug interaction with ethanol is anticipated to be low.

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Section: Discussionsupporting

confidence: 74%

Section: Discussioncontrasting

confidence: 50%

In Vitro Hydrolysis and Transesterification of CDP323, an α4β1/α4β7 Integrin Antagonist Ester Prodrug

et al. 2013

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“…3). In an analogous fashion, ethanol has been reported to elevate cocaine exposure (Perez-Reyes, 1994;Farre et al, 1997) while serving as a transesterification substrate yielding CES1-mediated cocaethylene in humans (Herbst et al, 2011) and in other species (Roberts et al, 1993;Hedaya and Pan, 1996;Parker and Laizure, 2010). The significant elevation of heart rate upon combining ethanol with either dl-MPH or d-MPH (Fig.…”

mentioning

confidence: 95%

Differential Influences of Ethanol on Early Exposure to Racemic Methylphenidate Compared with Dexmethylphenidate in Humans

et al. 2012

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Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1-2%. Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH). The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPH to l-EPH. Twenty-four healthy volunteers received dl-MPH (0.3 mg/kg) or d-MPH (0.15 mg/kg), with or without ethanol (0.6 g/kg). During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44-99%; P < 0.005). Furthermore, immediately following the ethanol drink the subjective effects of "high," "good," "like," "stimulated," and overall "effect" were significantly potentiated (P £ 0.01). Plasma l-EPH concentrations exceeded those of l-MPH. Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanolinduced potentiation of subjective effects was delayed relative to dl-MPH-ethanol. These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d-MPH. Ethanol increased the d-MPH area under the curve (AUC) 0-inf by 21% following dl-MPH (P < 0.001) and 14% for d-MPH (P = 0.001). In men receiving d-MPH-ethanol, the d-MPH absorption partial AUC 0.5-2 hours was 2.1 times greater and the time to maximum concentration (T max ) occurred 1.1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction. More rapid absorption of d-MPH carries implications for increased abuse liability.

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“…A growing body of evidence suggests that a number of factors can affect the catalytic activity of CES1 and CES2 and result in changes in drug disposition . One such factor is drug interactions that inhibit carboxylesterase function (Parker and Laizure, 2010;Zhu et al, 2010;Rhoades et al, 2012). It is well established that alcohol is an inhibitor of carboxylesterase-mediated cocaine hydrolysis (Farre et al, 1997;Cami et al, 1998;Song et al, 1999;Laizure et al, 2003;Parker and Laizure, 2010).…”

Section: Introductionmentioning

confidence: 99%

Identification of Carboxylesterase-Dependent Dabigatran Etexilate Hydrolysis

et al. 2013

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Dabigatran etexilate (DABE) is an oral prodrug that is rapidly converted to the active thrombin inhibitor, dabigatran (DAB), by serine esterases. The aims of the present study were to investigate the in vitro kinetics and pathway of DABE hydrolysis by human carboxylesterase enzymes, and the effect of alcohol on these transformations. The kinetics of DABE hydrolysis in two human recombinant carboxylesterase enzymes (CES1 and CES2) and in human intestinal microsomes and human liver S9 fractions were determined. The effects of alcohol (a known CES1 inhibitor) on the formation of DABE metabolites in carboxylesterase enzymes and human liver S9 fractions were also examined. The inhibitory effect of bis(4-nitrophenyl) phosphate on the carboxylesterase-mediated metabolism of DABE and the effect of alcohol on the hydrolysis of a classic carboxylesterase substrate (cocaine) were studied to validate the in vitro model. The ethyl ester of DABE was hydrolyzed exclusively by CES1 to M1 (K m 24.9 6 2.9 mM, V max 676 6 26 pmol/min per milligram protein) and the carbamate ester of DABE was exclusively hydrolyzed by CES2 to M2 (K m 5.5 6 0.8 mM; V max 71.1 6 2.4 pmol/min per milligram protein). Sequential hydrolysis of DABE in human intestinal microsomes followed by hydrolysis in human liver S9 fractions resulted in complete conversion to DAB. These results suggest that after oral administration of DABE to humans, DABE is hydrolyzed by intestinal CES2 to the intermediate M2 metabolite followed by hydrolysis of M2 to DAB in the liver by CES1. Carboxylesterase-mediated hydrolysis of DABE was not inhibited by alcohol.

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The Effect of Ethanol on Oral Cocaine Pharmacokinetics Reveals an Unrecognized Class of Ethanol-Mediated Drug Interactions

Cited by 34 publications

References 39 publications

In Vitro Hydrolysis and Transesterification of CDP323, an α4β1/α4β7 Integrin Antagonist Ester Prodrug

In Vitro Hydrolysis and Transesterification of CDP323, an α4β1/α4β7 Integrin Antagonist Ester Prodrug

Differential Influences of Ethanol on Early Exposure to Racemic Methylphenidate Compared with Dexmethylphenidate in Humans

Identification of Carboxylesterase-Dependent Dabigatran Etexilate Hydrolysis

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