Cocaine, norcocaine, ecgonine methylester and benzoylecgonine pharmacokinetics in the rat

Mets, Berend; Diaz, Julia M.; Soo, E.; Jamdar, Subhash C.

doi:10.1016/s0024-3205(99)00367-7

Cited by 29 publications

(19 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The large increase in the oral bioavailability of cocaine (F increased from 0.18 to 0.72) demonstrates the potent inhibitory effect of ethanol on catalytic hydrolysis and implicates ethanol in a broad class of drug interactions encompassing numerous important therapeutic agents that have carboxylesterase-dependent metabolism. The hydrolysis of cocaine predominantly to BE and EME has been reported in rats, pigs, monkeys, and humans (Kambam et al, 1992;Saady et al, 1995;Cone et al, 1998;Mets et al, 1999;Evans and Foltin 2004). When cocaine is given by the intravenous or intraperitoneal route, BE is the most abundant metabolite formed followed by EME.…”

Section: Discussionmentioning

confidence: 99%

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

Parker

Laizure

2010

Drug Metabolism and Disposition

View full text Add to dashboard Cite

ABSTRACT:Ethanol decreases the clearance of cocaine by inhibiting the hydrolysis of cocaine to benzoylecgonine and ecgonine methyl ester by carboxylesterases, and there is a large body of literature describing this interaction as it relates to the abuse of cocaine. In this study, we describe the effect of intravenous ethanol on the pharmacokinetics of cocaine after intravenous and oral administration in the dog. The intent is to determine the effect ethanol has on metabolic hydrolysis using cocaine metabolism as a surrogate marker of carboxylesterase activity. Five dogs were administered intravenous cocaine alone, intravenous cocaine after ethanol, oral cocaine alone, and oral cocaine after ethanol on separate study days. Cocaine, benzoylecgonine, and cocaethylene concentrations were determined by high-performance liquid chromatography. Cocaine had poor systemic bioavailability with an area under the plasma concentration-time curve that was approximately 4-fold higher after intravenous than after oral administration. The coadministration of ethanol and cocaine resulted in a 23% decrease in the clearance of intravenous cocaine and a 300% increase in the bioavailability of oral cocaine. Cocaine behaves as a high extraction drug, which undergoes first-pass metabolism in the intestines and liver that is profoundly inhibited by ethanol. We infer from these results that ethanol could inhibit the hydrolysis of other drug compounds subject to hydrolysis by carboxylesterases. Indeed, there are numerous commonly prescribed drugs with significant carboxylesterase-mediated metabolism such as enalapril, lovastatin, irinotecan, clopidogrel, prasugrel, methylphenidate, meperidine, and oseltamivir that may interact with ethanol. The clinical significance of the interaction of ethanol with specific drugs subject to carboxylesterase hydrolysis is not well recognized and has not been adequately studied.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Parker

Laizure

2010

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…bolus administration (0.5-5 mg/kg) in rats (Booze et al, 1997;Hedaya and Pan, 1997;Lau et al, 1999;Mets et al, 1999). Because the PK estimates of i.v.…”

Section: Downloaded Frommentioning

confidence: 99%

The Pharmacokinetic Determinants of the Frequency and Pattern of Intravenous Cocaine Self-administration in Rats by Pharmacokinetic Modeling

Lau¹,

Sun²

2002

Drug Metabolism and Disposition

View full text Add to dashboard Cite

ABSTRACT:We investigated the pharmacokinetic determinants of the frequency of intravenous cocaine self-administration in 2.5-h sessions. Two groups of rats were implanted with dual catheters that permitted cocaine infusion and blood sampling via the femoral and jugular vein catheters, respectively. Half of the animals in each group self-administered one of the two cocaine unit doses (0.5 and 1 mg/kg/infusion) by pressing a lever under a continuous schedule of reinforcement. To monitor serum cocaine concentrations, the remaining animals received concurrent, response-independent infusions whenever the matched animals self-administered cocaine infusions. Multiple concentration-time data in two successive selfadministrations were determined to monitor the extent of fluctuation in concentrations by pharmacokinetic modeling. Behavioral analyses revealed the higher unit dose (1 mg/kg) resulted in less frequent cocaine self-administration, and a longer interinfusion interval, whereas the total doses were similar for the two groups (24.5-27.0 mg/kg/2.5 h). Cocaine decayed biexponentially. Both the values of clearance and terminal elimination rate constant for the self-administration paradigm were significantly greater than those after the bolus cocaine dosing series (0.5 and 1 mg/kg, separated by 3 days). The regularity in cocaine self-administration produced relatively stable serum cocaine concentrations that oscillated between maximum (C max ) and minimum (C min ) values regardless of dose size and interinfusion interval. Although the C max for the 1-mg/kg unit dose (1.47 g/ml) was significantly higher than that for the 0.5-mg/kg dose (0.82 g/ml), the C min values between the groups approximated each other (0.28, and 0.34 g/ml, respectively). Hence, the C min is the determinant of the initiation of the next drug-taking behavior.Intravenous cocaine self-administration was first demonstrated in rats in 1968 (Pickens andThompson, 1968). In that study, rats implanted with i.v. cannulas were placed in operant chambers where each lever-press response (i.e., fixed ratio 1 schedule) produced an infusion of a fixed dose of cocaine (e.g., 1 mg/kg/infusion). The resulting self-infusion behavior was viewed as an example of operant conditioning, in which the drug infusion served as a reinforcer for responses leading to its presentation. The results indicated that the number of infusions varied inversely in an almost linear manner with the size of the unit dose. That is, as the unit dose was increased, the number of infusions decreased and the interinfusion interval increased. As a result, the total self-administered drug dose remained relatively similar across different unit doses. The inverse relationship between the frequency of drug self-administration and unit dose also has been shown in studies of cocaine and other drugs of abuse (e.g., morphine, amphetamine) by using various schedules of reinforcement in mice (David et al., 2001), rats (Carroll et al., 1981;Caine et al., 1999), monkeys (Goldberg et al., 1971;Wilson et al., 19...

show abstract

“…Este produto de biotransformação é uma hepatotoxina e também é distribuído para o cérebro, sendo farmacologicamente ativo (METS et al, 1999).…”

Section: Eliminaçãounclassified

“…Assim, a biotransformação origina vários metabólitos, principalmente a benzoilecgonina (BE), cerca de 45%, e o éster metilecgonina, cerca de 40%, sendo produzidos em menor porcentagem norcocaína, ecgonina, benzoilnorcocaína e n-hidroxinorcocaína (METS et al, 1999).…”

Section: Eliminaçãounclassified

“…Este produto de biotransformação é uma hepatotoxina e também é distribuído para o cérebro, sendo farmacologicamente ativo (METS et al, 1999). A meia-vida plasmática de eliminação da COC, considerando modelo bicompartimental, situa-se entre 2,7 e 7,3 horas para a via intranasal, e entre 2,7 -6,3 horas e 2,4 -5,8 minutos para a via respiratória e intravenosa, respectivamente (CONE, 1998).…”

Section: Eliminaçãounclassified

See 1 more Smart Citation

Redistribuição da cocaína e sua influência na neuroquímica post mortem

Carvalho¹

View full text Add to dashboard Cite

Redistribuição da cocaína e sua influência na neuroquímica post mortem À Profª Dra. Alice Aparecida da Matta Chasin pela orientação na elaboração do projeto sobre redistribuição post mortem e pelas valiosas sugestões na realização desta obra. À Profª Dra. Maria Amélia Zogno e ao Departamento de Reprodução Animal da FMVZ/USP pela concessão de uso do equipamento de cromatografia líquida de alta eficiência acoplada ao detector de arranjo de diodos.À banca de qualificação, composta pelos Professores Doutores Irene Videira de Lima, Regina Lúcia de Moraes Moreau e Luís Roberto de Oliveira Fontes pelas importantes críticas e sugestões. À Profª Dra. Marina F. M. Tavares do Instituto de Química da USP por permitir a realização dos testes em eletroforese capilar na etapa de seleção do método analítico para identificação e quantificação de cocaína e benzoilecgonina. A interpretação dos achados laboratoriais no estabelecimento da causa mortis consiste na integração dos conhecimentos sobre a toxicocinética e toxicodinâmica do agente, conhecimentos de sua redistribuição post mortem (RPM) e achados necroscópicos que possibilitem o nexo causal entre o toxicante e o efeito letal. Neste sentido, é importante considerar que somente as concentrações de cocaína (COC) e seus metabólitos podem não ser determinantes na interpretação da causa de morte, podendo ser útil o cotejamento com outros parâmetros, como os níveis de neurotrasmissores que representem o mecanismo de ação do fármaco. Assim, este trabalho teve por objetivo investigar a RPM da COC e seu metabólito benzoilecgonina (BE) em três segmentos do tecido encefálico (TE), no humor vítreo (HV) e sangue (SG), bem como determinar as concentrações de catecolaminas e indolaminas no encéfalo para avaliar a aplicação da neuroquímica post mortem (NPM) na toxicologia forense. No estudo de RPM foram quantificados os níveis de COC e BE em três segmentos do TE (córtex frontal, núcleos da base e cerebelo), no HV e no SG através de método por cromatografia líquida de alta eficiência (HPLC) acoplada ao detector de arranjo de diodos. Os estudos de neuroquímica foram realizados empregando-se HPLC acoplada ao detector eletroquímico. Os resultados indicaram que as concentrações médias de COC foram maiores no TE, seguido por SG e HV (3,09, 2,92 e 1,71 µg/mL, respectivamente), enquanto para BE foram maiores em SG, seguido por HV e TE (6,12, 1,39 e 0,87 µg/mL, respectivamente).As concentrações de COC se apresentaram distribuídas uniformemente nos três segmentos de TE e apresentaram alta correlação com o HV. Adicionalmente, a média de concentrações de dopamina total foi maior no grupo de indivíduos com amostras positivas para COC, sendo verificado diferença significativa entre este grupo e o de indivíduos com amostras negativas para o fármaco de interesse. Os resultados demostraram que o estudo de RPM e da NPM constituem ferramentas aplicáveis na interpretação da causa e maneira de morte. In case of intoxication, the interpretation of analytical results to assess the cause and process of death requir...

show abstract

Cocaine, norcocaine, ecgonine methylester and benzoylecgonine pharmacokinetics in the rat

Cited by 29 publications

References 25 publications

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

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

The Pharmacokinetic Determinants of the Frequency and Pattern of Intravenous Cocaine Self-administration in Rats by Pharmacokinetic Modeling

Redistribuição da cocaína e sua influência na neuroquímica post mortem

Contact Info

Product

Resources

About