Dose-response cocaine pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized, freely moving male rats

R. M. Booze, A. F. Lehner, D. R. Wallace, M. A. Welch, C. F. Mactutus

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Despite the wealth of experimental data on cocaine abuse, there are no published dose-response pharmacokinetic studies with bolus IV cocaine injection in the male rat. The present study examined the pharmacokinetics of arterial plasma concentrations of cocaine and metabolite profile [benzoylecgonine (BE), ecgonine methyl ester (EME), norcocaine (NC)] following a single IV injection of 0.5, 1.0, or 3.0 mg/kg cocaine. Male Sprague-Dawley rats (N = 25) were anesthetized and surgically instrumented with both jugular vein (drug administration) and carotid artery (blood withdrawal) catheters and allowed to recover for at least 24 h. Arterial plasma samples (200 μl) were obtained at eight time points (0.5, 1, 1.5, 2, 5, 10, 20, 30 min) following IV bolus injection (15-s injection, 15-s flush) and analyzed by single ion monitoring using GC/MS. Nonlinear regression and noncompartmental pharmacokinetic analysis were employed. Mean ± SEM peak plasma concentrations of cocaine occurred at 30 s in a dose-response manner (370 ± 14, 755 ± 119, 2553 ± 898 ng/ml for 0.5, 1.0, and 3.0 mg/kg groups, respectively). T( 1/4 α) was < 1 min for all groups, but inversely related to dose. T( 1/4 β) was independent of dose (13.3 ± 1.6, 13.0 ± 1.5, and 12.0 ± 2.0 min for 0.5, 1.0, and 3.0 mg/ kg groups, respectively). MRT (16.0, 15.9, 14.5 min), Vd(SS) (3.3, 3.2, and 2.8 l/kg), and Cl(TOT) (204, 201, and 195 ml/min/kg) also provided little evidence of dose-dependent effects. Although the metabolic profile of IV cocaine was similarly ordered for all dose groups (BE > EME > NC), a quantitative shift in metabolite profile was evident as a function of increasing dose. This metabolic shift, perhaps attributable to saturation of plasma and liver esterases, suggests that the recently reported pharmacodynamic effects positively correlated with IV cocaine dose are unlikely attributable to NC, a minor but pharmacologically active metabolite. In sum, the IV pharmacokinetic profile in rats is distinct from that observed via the SC, IP, and PO routes of administration and offers the potential to provide a reasonable clinically relevant rodent model.

Original languageEnglish
Pages (from-to)7-15
Number of pages9
JournalNeurotoxicology and Teratology
Issue number1
Publication statusPublished - 1 Jan 1997



  • Benzoylecgonine
  • Cocaine
  • Drug administration routes
  • Ecgonine methyl ester
  • Norcocaine
  • Pharmacokinetics
  • Rats, Sprague-Dawley

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