Mass Spectrometric Studies of Cocaine Disposition in Animals and Humans Using Stable Isotope-Labeled Analogues

Jindal, Satya P.; Lutz, Theresa

doi:10.1002/jps.2600781208

Cited by 34 publications

(11 citation statements)

References 29 publications

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“…The metabolism of some of the more frequently prescribed and self-administered drugs has been systematically analyzed across species. The metabolic profile of cocaine was found to be similar in humans and in rats, as shown in a study utilizing ion cluster technique and gas chromatography-mass spectrometry (Jindal and Lutz, 1989). The metabolic profile of different doses of radiolabeled amphetamine, as measured by metabolites in urine and feces, was found to be similar among monkeys (0.66 mg/kg p.o.…”

Section: Pharmacokineticsmentioning

confidence: 69%

Psychostimulants and Cognition: A Continuum of Behavioral and Cognitive Activation

et al. 2013

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Section: Pharmacokineticsmentioning

confidence: 69%

Psychostimulants and Cognition: A Continuum of Behavioral and Cognitive Activation

et al. 2013

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“…and indicate that P-450 3A plays a major role in the déméthyl ation of cocaine, but not in the hydroxylation of norcocaine. N-Hydroxynorcocaine has been detected previously in human urine [20], and Roberts et al [21] tentatively identified N-hydroxynorcocaine as a human hepatic microsomal metabolite by comparison of HPLC retention time with that of an authentic standard. How ever, the chemical identity of N-hydroxynorcocaine produced by human liver microsomes had not been established prior to this report.…”

Section: Resultsmentioning

confidence: 99%

Norcocaine and N-Hydroxynorcocaine Formation in Human Liver Microsomes: Role of Cytochrome P-450 3A4

et al. 1993

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Cocaine was metabolized to norcocaine by microsomes prepared from lymphoblastoid cells expressing transfected human P-450 3A4. The specific activities of norcocaine formation by microsomes prepared from three human liver samples correlated with the amount of P-450 3A immunoreactive protein detected by immunoblot. Triacetyloleandomycin, a specific inhibitor of P-450 3A isoforms, inhibited formation of norcocaine from cocaine, but not formation of N-hydroxynorcocaine from norcocaine. The chemical identity of the norcocaine and N-hydroxynorcocaine produced by human liver microsomes was established by combination of gas chromatography and mass spectrometry. Thus, human P-450 3A4 is a cocaine demethylase, and P-450 isoforms of the 3 A family are responsible for the majority of norcocaine production by human hepatic microsomes.

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“…Cocaine (n 5) Saline (n 6) P Jindal & Lutz 1989 identi®ed cocaine and the three metabolites studied here, and a further 6 metabolites, in rat urine after 20 mg kg À1 cocaine administered intraperitoneally. Misra et al (1979) noted that only 1% of administered norcocaine was retrieved from urine.…”

Section: Parametermentioning

confidence: 92%

Chronic Continuous Cocaine Infusion in Rats: Effect on Urine Cocaine, Ecgonine Methylester and Benzoylecgonine Concentrations and Bolus-dose Cocaine Pharmacokinetics

Mets

Soo

Diaz

et al. 2000

Journal of Pharmacy and Pharmacology

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The aim of this study was to determine the effect of chronic cocaine infusion on urine cocaine, ecgonine methylester and benzoylecgonine concentrations to establish if they varied with dose and duration of cocaine administration. Male rats were continuously infused with cocaine at either 6 or 18 mg kg(-1) daily for 13 days. Three urine samples taken over the course of the infusion period showed that cocaine, ecgonine methylester and benzoylecgonine concentrations varied with the dose administered and the duration of administration. Cocaine, ecgonine methylester and benzoylecgonine concentrations were 2-3 times greater in the high-dose group than the low-dose group at each sampling time point. These decreased, respectively, from 7.0+/-1.1, 26.7+/-4.5 and 29.5+/-5.4 microg mL(-1) to 2.5+/-0.5, 10.5+/-1.8 and 11.8+/-1.5 microg mL(-1) in the high-dose group and from 1.0+/-0-2, 7.8+/-1.5 and 6.3+/-0.1 microg mL(-1) to 0.5+/-0.1, 4.0+/-0.6 and 3.1+/-0.4 microg mL(-1) in the low-dose group (P < 0.05) over the infusion period. We also studied the pharmacokinetic and metabolic profile of an intravenous bolus dose of 2.5 mg kg(-1) cocaine hydrochloride after a similar cocaine infusion in rats. Cocaine pharmacokinetics and the profile of ecgonine methylester, benzoylecgonine and norcocaine were no different from rats chronically infused with saline for the same period. Altered cocaine metabolism could not explain the effect of the duration of cocaine infusion on altered metabolite concentrations in urine. Ecgonine methylester/benzoylecgonine urine concentration ratios did not alter with duration of infusion (1.2+/-0.2 and 1.1+/-0.2 in the high-dose group at the first and last time point) and were not affected by the dose of cocaine (1.3+/-0.6 and 1.2+/-0.1 at corresponding times in the low-dose group (P > 0.05)). We conclude that chronic cocaine infusion does not alter cocaine metabolism. This was not reflected by absolute cocaine metabolite urine concentrations, which varied with time, but was represented by urine ecgonine methyl ester/benzoylecgonine concentration ratios.

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Mass Spectrometric Studies of Cocaine Disposition in Animals and Humans Using Stable Isotope-Labeled Analogues

Cited by 34 publications

References 29 publications

Psychostimulants and Cognition: A Continuum of Behavioral and Cognitive Activation

Psychostimulants and Cognition: A Continuum of Behavioral and Cognitive Activation

Norcocaine and N-Hydroxynorcocaine Formation in Human Liver Microsomes: Role of Cytochrome P-450 3A4

Chronic Continuous Cocaine Infusion in Rats: Effect on Urine Cocaine, Ecgonine Methylester and Benzoylecgonine Concentrations and Bolus-dose Cocaine Pharmacokinetics

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