Evaluation of dose-dependent pharmacokinetics of cocaethylene and cocaine in conscious dogs.
Cocaine use continues to be widespread in the United States. Most cocaine users co-ingest ethanol resulting in decreased elimination of cocaine and formation of the active cocaine metabolite, cocaethylene, by hepatic carboxylesterases. In a recent study from our laboratory in dogs to evaluate the cocaine-ethanol interaction, we demonstrated a similar ethanol-induced reduction in cocaine metabolism, although we were unable to detect cocaethylene when the two drugs were given together. This unexpected finding could be explained by ethanol-induced inhibition of cocaine metabolism via a pathway that does not involve hepatic carboxylesterases or formation of cocaethylene that inhibits cocaine metabolism and is then rapidly cleared. The purpose of the present study is to determine which of these mechanisms best explain our data by characterizing the pharmacokinetics of cocaine and cocaethylene over a range of doses in conscious dogs. Seven adult mongrel dogs received 1, 3, and 5 mg/kg cocaine and cocaethylene HCl base with each drug dose administered i.v. on a separate study day. Arterial blood samples were collected at various times after each dose and analyzed for cocaine and cocaethylene by HPLC. Cocaine clearance was dose-dependent with clearance decreasing from 1.53 +/- 0.31 to 1.09 +/- 0.11 l/min as the dose was increased from 1 to 5 mg/kg (p<0.05). Vmax x Vss and Km for cocaine were 0.95 +/- 0.40 l/min/kg and 11.2 +/- 6.2 mg/kg, respectively. Cocaethylene pharmacokinetics were similar to those of cocaine, but were not dose-dependent over the dose range of 1-5 mg/kg. These results suggest that cocaethylene is not formed and rapidly cleared after co-administration of cocaine and ethanol to the dog, but rather suggests that cocaethylene is not formed in appreciable quantities in the dog. Therefore, we conclude that the decrease in cocaine elimination in the dog associated with ethanol administration is due to ethanol-mediated inhibition cocaine metabolism, rather than inhibition by cocaethylene.
Parker
R B
RB
Department of Clinical Pharmacy, The University of Tennessee, Memphis, 38163, USA. rparker@utmem1.utmem.edu
Laizure
S C
SC
Williams
C L
CL
Mandrell
T D
TD
Lima
J J
JJ
D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D018765:Dopamine Uptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005069:Evaluation Studies as Topic; D008657:Metabolic Clearance Rate
D018765:Dopamine Uptake Inhibitors; C066444:cocaethylene; D003042:Cocaine