Determination of Pharmacokinetics of Cocaine in Sheep by Liquid Chromatography

Khan, Muhammad Farid; Gupta, Pramod; Cristie, R.; Nangia, Avinash; Winter, Helen; Lam, F.C.; Perrier, Donald; Hung, C.T.

doi:10.1002/jps.2600760112

Cited by 28 publications

(12 citation statements)

References 25 publications

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“…The mean elimination half-lives be tween 4.0 and 5.6 min in fetus and ewe (ta ble 1) confirm the rapid elimination re ported by Moore et al [8] and Khan et al [7] in this species (range: 6.6-12.9 min). While our finding of somewhat shorter half-life val ues than previously reported could be an artifact of cholinesterase-mediated hydroly sis of cocaine, all blood samples were hepa rinized, and the pH was reduced imme diately after collection.…”

Section: Discussionsupporting

confidence: 72%

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Disposition of Cocaine in Pregnant Sheep: I. Pharmacokinetics

Dj²,

Rm³

et al. 1991

Dev Pharmacol Ther

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Cocaine abuse by pregnant women is increasingly recognized as causing serious health consequences for mother and newborn. To assess the placental transfer and fetal effects of cocaine, we studied its pharmacokinetics following intravenous administration to the pregnant ewe and fetus. Following bolus doses of 0.5-4.0 mg/kg to ewes, cocaine appeared within 30 s in fetal circulation, with peak concentrations occurring in 4-5 min. The disappearance of cocaine in the fetal plasma paralleled that in maternal plasma, suggesting that a rapid equilibrium of cocaine occurred between maternal and fetal compartments. The mean half-life of cocaine in the fetus across doses (4.4-5.0 min) was similar to that in the ewe (4.0-5.6 min). Plasma clearance of cocaine in the ewe did not appear to vary according to dose. The fetal exposure to cocaine, as indicated by the area under the fetal plasma concentration versus curve, was a linear function of maternal cocaine dose (r = 0.96, p < 0.01). These results demonstrate rapid placental transfer of cocaine after maternal administration in an animal model and rapid metabolism by mother and fetus.

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Section: Discussionsupporting

confidence: 72%

“…This was reported by Khan et al [7], How ever, there was no apparent difference in body clearance between the doses of 1.0 and 4.0 mg/kg (table 1). The lack of linearity with maternal AUC may be an artifact due to the lack of data between 30 s and 4 min.…”

Section: Discussionsupporting

confidence: 60%

Disposition of Cocaine in Pregnant Sheep: I. Pharmacokinetics

Dj²,

Rm³

et al. 1991

Dev Pharmacol Ther

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“…This indicates that methylecgonidine, like cocaine, distributes from blood to other tissues. The mean volume of distribution of 4 mg/kg cocaine in sheep is 3.11 l/kg, and the volumes of distribution of 3 mg/kg methylecgonidine for sheep 1 and 2 were 10.0 and 6.6 l/kg, respectively (Khan et al, 1987). Calculation of z-scores confirms that both sheep Fig.…”

mentioning

confidence: 57%

“…‫,ء‬ p Ͻ 0.05 and ‫,ءء‬ p Ͻ 0.005, significant differences by paired t test. The mean half-lives for 1, 2, and 4 mg/kg cocaine in sheep were 8.9, 10.5, and 10.6 min, respectively (Khan et al, 1987). The lower confidence intervals for half-lives at 3 mg/kg methylecgonidine were 16.3 and 17.8 for sheep 1 and 2, respectively.…”

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confidence: 88%

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Pharmacokinetics and Pharmacodynamics of Methylecgonidine, a Crack Cocaine Pyrolyzate

Scheidweiler¹,

Plessinger²,

Shojaie³

et al. 2003

J Pharmacol Exp Ther

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Methylecgonidine is formed from cocaine base when smoked and has been identified in biological fluids of crack smokers. Ecgonidine, a metabolite of methylecgonidine formed via esterase activity, also has been identified in similar samples collected from crack smokers. Methylecgonidine and ecgonidine can be used as biomarkers to differentiate smoking from cocaine use via other routes of administration. We determined the pharmacokinetic properties of methylecgonidine and ecgonidine in sheep after intravenous administration of methylecgonidine at doses of 3.0, 5.6, and 10.0 mg/kg using gas chromatography-mass spectrometric assays. Methylecgonidine clears quickly from blood with a half-life of 18 to 21 min, whereas ecgonidine has a longer half-life of 94 to 137 min. Because ecgonidine clears more slowly, it may be a more effective biomarker of cocaine smoking. The cardiovascular stimulant effects of cocaine contrast with reported in vitro muscarinic agonist effects of methylecgonidine, decreasing contractility and stimulating nitric oxide production in cardiac cells and tissues. To test the hypothesis that methylecgonidine produces cardiovascular effects in vivo consistent with muscarinic agonism, methylecgonidine was administered to sheep intravenously (0.1-3.0 mg/kg) while monitoring heart rate and blood pressure. Significant hypotension and tachycardia occurred in all three sheep. Two of the three sheep demonstrated mild bradycardia 3 to 5 min after methylecgonidine injection. Intravenous pretreatment with atropine methyl bromide (15 g/kg) antagonized methylecgonidine-induced hypotension in all three sheep, supporting the hypothesis that methylecgonidine acts as a muscarinic agonist in vivo.Heating cocaine base (smoking crack) produces the pyrolyzate methylecgonidine (anhydroecgonine methylester). Because methylecgonidine is produced via thermal conversion from cocaine, it can be used as a marker to differentiate between smoking and cocaine use via other routes of administration. In forensic cases, methylecgonidine has been detected in urine (Jacob et al

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Role of the red blood cell in drug metabolism

Cossum¹

1988

Biopharm & Drug Disp

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Determination of Pharmacokinetics of Cocaine in Sheep by Liquid Chromatography

Cited by 28 publications

References 25 publications

Disposition of Cocaine in Pregnant Sheep: I. Pharmacokinetics

Disposition of Cocaine in Pregnant Sheep: I. Pharmacokinetics

Pharmacokinetics and Pharmacodynamics of Methylecgonidine, a Crack Cocaine Pyrolyzate

Role of the red blood cell in drug metabolism

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