Concentration of Cocaine and Metabolites in Plasma of Humans Following Intravenous Administration and Smoking of Cocaine

Isenschmid, Daniel S.; Fischman, Marian W.; Foltin, Richard W.; Caplan, Yale H.

doi:10.1093/jat/16.5.311

Cited by 79 publications

(37 citation statements)

References 5 publications

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“…It is possible that women were not metabolizing cocaine as efficiently as men, and had we continued to measure plasma concentrations, benzoylecgonine plasma concentrations may have continued to rise in women as compared to men. To our knowledge, only one other study, conducted in men, measured cocaine and benzoylecgonine plasma concentrations after repeated doses of cocaine (Isenschmid et al 1992). They found that after the last cocaine dose, cocaine and benzoylecgonine plasma concentrations were similar to each other, which was also observed in the present study.…”

Section: Discussionsupporting

confidence: 88%

Limited Sex Differences in Response to “Binge” Smoked Cocaine Use in Humans

Evans¹,

Haney

Fischman

et al. 1999

Neuropsychopharmacology

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The subjective and physiological effects of repeated smoked cocaine self-administration were compared in 11 men and 9 women. Twice a day, on 2 consecutive days, participants smoked up to six 50-mg doses of cocaine base, at 14 min intervals. Men and women self-administered a similar number of cocaine doses (21.7 and 21.6, respectively Although women make up as much as one-third of the cocaine-abusing population (USDHHS 1993), relatively few preclinical or clinical studies have investigated sex differences in response to cocaine administration. Among the laboratory animal literature, some studies have found no or few cocaine-related sex differences (e.g., Foltin and Schuster 1982;van Haaren and Hughes 1990;Haney et al. 1995;Craft and Stratmann 1996). Although other studies have documented sex differences, the question of whether female rodents are more or less sensitive to the effects of cocaine has not been resolved. For example, cocaine administration increased locomotor activity more in intact female rats (van Haaren and Meyer 1991;Haney et al. 1994) than in either ovariectomized female rats or male rats (either intact or castrated); whereas, cocaine increased locomotor activity less in female mice than in male mice (Morse et al. 1993). However, Morishima et al. (1993) showed that male rats and ovariectomized female rats were more sensitive to the toxic effects of cocaine than intact females. With respect to cocaine self-administration, no sex, hormonal, or estrous cycle differences have been observed under a fixed ratio one schedule of intravenous cocaine self-administration (Dalton et al. 1986;Roberts et al. 1987Roberts et al. , 1989Haney et al. 1995). However, the dopamine antagonist haloperidol increased cocaine self-administration more in female than in male rats (Dalton et al. 1986). In addition, the effect of haloperidol on cocaine self-administration varied across the estrous cycle and was reduced in ovariectomized females (Roberts et al. 1987). Furthermore, when a progressive-ratio schedule of reinforcement was employed, sex differences in cocaine self-administration were observed; female rats had higher breakpoints than male rats, particularly during the estrus phase (Roberts et al. 1989).

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Section: Discussionsupporting

confidence: 88%

Limited Sex Differences in Response to “Binge” Smoked Cocaine Use in Humans

Evans¹,

Haney

Fischman

et al. 1999

Neuropsychopharmacology

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“…Unfortunately, in the elegant cocaine pharmacokinetic study by Mendelson et al (1999b) cocaine metabolite levels were not reported. Other studies in men have shown that BZE levels continue to rise approximately 75 min after the last cocaine dose (Isenschmid et al, 1992) and can remain elevated and relatively stable 1-6 h after a single i.v. dose of cocaine (Cone, 1995).…”

Section: Pharmacokinetics Of the Cocaine Metabolites Bze And Emementioning

confidence: 91%

Pharmacokinetics of Intravenous Cocaine Across the Menstrual Cycle in Rhesus Monkeys

Evans

Foltin

2004

Neuropsychopharmacol

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Several studies in rodents suggest that there are sex differences in response to cocaine that are related to fluctuations in the ovarian hormones of females. Female rhesus monkeys have menstrual cycles that are remarkably similar to human menstrual cycles in both duration and hormonal variations. Therefore, data obtained in monkeys should be an ideal model for assessing the effects of cocaine across the menstrual cycle in humans. The present study assessed the acute effects of intravenous cocaine (0, 0.25, 0.50, and 1.00 mg/kg) in five female rhesus monkeys during four phases of the menstrual cycle: menses, midfollicular, periovulatory, and midluteal. To reduce the effects of stress that can occur from sedation, all animals were trained to enter primate chairs so that repeated blood samples could be obtained in awake animals. Hormone levels for estradiol and progesterone were measured each session before cocaine administration. Cocaine and cocaine metabolite plasma levels were measured at 5, 15, 30, 45, 60, and 90 min after cocaine administration. Similarly, levels of luteinizing hormone (LH) were measured before, 15, 30, 45, 60, and 90 min after cocaine administration. Within 5 min of cocaine administration, cocaine plasma levels peaked and dose-dependent behavioral changes (ie increased motor activity, mydriasis, and refusal of treats) were observed. These effects typically resolved in 15-30 min. There were few differences in the pharmacokinetic profile of cocaine across the menstrual cycle. However, the cocaine metabolites, BZE and EME, did vary across the menstrual cycle, with both being increased in the luteal phase, particularly following the highest dose of cocaine. In addition, unlike previous studies, cocaine did not produce consistent increases in LH levels. Rather, the change in LH levels depended on menstrual cycle phase and cocaine dose. In summary, there is little evidence that the pharmacokinetics of cocaine vary as a function of menstrual cycle phase.

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“…A lthough cocaine binds only transiently to its receptors and is cleared rapidly from plasma (1,2), some of its effects persist after weeks or even months of abstinence (3)(4)(5). Persistence of effects could be caused by cellular mechanisms (6, 7) but also by direct chemical modification of proteins.…”

mentioning

confidence: 99%

“…Cocaine is cleared from plasma in humans through hydrolysis of its ester groups (2). Benzoyl ester hydrolysis is mediated by various enzymes, but significant hydrolysis of the methyl ester occurs spontaneously under physiologic conditions.…”

mentioning

confidence: 99%

Covalent modification of proteins by cocaine

Deng

Bharat²,

Fischman³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Cocaine covalently modifies proteins through a reaction in which the methyl ester of cocaine acylates the -amino group of lysine residues. This reaction is highly specific in vitro, because no other amino acid reacts with cocaine, and only cocaine's methyl ester reacts with the lysine side chain. Covalently modified proteins were present in the plasma of rats and human subjects chronically exposed to cocaine. Modified endogenous proteins are immunogenic, and specific antibodies were elicited in mouse and detected in the plasma of human subjects. Covalent modification of proteins could explain cocaine's autoimmune effects and provide a new biochemical approach to cocaine's long-term actions.

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Concentration of Cocaine and Metabolites in Plasma of Humans Following Intravenous Administration and Smoking of Cocaine

Cited by 79 publications

References 5 publications

Limited Sex Differences in Response to “Binge” Smoked Cocaine Use in Humans

Limited Sex Differences in Response to “Binge” Smoked Cocaine Use in Humans

Pharmacokinetics of Intravenous Cocaine Across the Menstrual Cycle in Rhesus Monkeys

Covalent modification of proteins by cocaine

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