TY - JOUR
T1 - Dose-response cocaine pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized, freely moving male rats
AU - Booze, R. M.
AU - Lehner, A. F.
AU - Wallace, D. R.
AU - Welch, M. A.
AU - Mactutus, C. F.
N1 - Funding Information:
This work was supported in part by grants from the National Institute of Health (DA06638, DA09160, and ES06259) and from the Commonwealth of Kentucky. The expert assistance of Dr. A. E. Mc-Crea, the thoughtful discussions with Drs. R. Dawson, Jr.. P. J. Mc-Namara, and W. Slikker, Jr., and the constructive comments of the journal referees are gratefully acknowledged. The Tobacco and Health Research Institute is an administrative unit of the University of Kentucky and is not affiliated with the Tobacco Research Council nor does it receive any financial support from the Tobacco Institute or the tobacco industry. A preliminary report of these findings has been presented at the 25th Annual Meeting of the Society for Neuroscience, San Diego, CA, November ll-16,199s. The authors dedicate this manuscript to the memory of Rhianon Booze Mactutus.
PY - 1997/1
Y1 - 1997/1
N2 - 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.
AB - 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.
KW - Benzoylecgonine
KW - Cocaine
KW - Drug administration routes
KW - Ecgonine methyl ester
KW - Norcocaine
KW - Pharmacokinetics
KW - Rats, Sprague-Dawley
UR - http://www.scopus.com/inward/record.url?scp=0030983078&partnerID=8YFLogxK
U2 - 10.1016/S0892-0362(96)00180-8
DO - 10.1016/S0892-0362(96)00180-8
M3 - Article
C2 - 9088006
AN - SCOPUS:0030983078
SN - 0892-0362
VL - 19
SP - 7
EP - 15
JO - Neurotoxicology and Teratology
JF - Neurotoxicology and Teratology
IS - 1
ER -