Purpose: Research on the psychostimulant cocaine has previously shown that genetic factors may influence liability for abuse and addiction, and initial sensitivity to psychostimulants can be used to predict subsequent misuse. Murine models of cocaine response, which utilize locomotor activation as a behavioral phenotype, have been used to model human initial psychostimulants sensitivity. An association between cocaine pharmacokinetic (PK) data and acute locomotor activation across 45 mouse strains has been previously described (PMID 25727211); however, this association alone cannot fully explain interstrain phenotypic differences (e.g., mouse behavior). The objective of the present study was to characterize the population PK of cocaine (COC) and its two metabolites, norcocaine (NOR), and benzoylecgonine (BZE) in mice after intraperitoneal administration of cocaine.
Methods: Six inbred mouse strains (l/LnJ, C57BL/6J, FVB/NJ, BTBR T+ tf/J, LG/J, LP/J) were selected based on previously-characterized phenotypic response differences to cocaine (total mice n=395). A total of four cocaine doses were administered intraperitoneally (5, 10, 30, and 40 mg/kg), with 15 mice in each dosing group per strain. Within each dosing group, mice were euthanized at five different time points (2, 5, 10, 30, and 60 min) to quantify COC, NOR, and BZE concentrations in the plasma and brain. Each strain, dose and time combination was repeated in triplicate. Median concentrations (n=790) were used for plot analyses, while the total number of concentrations (n=2370) and a sparse sampling approach were used for non-compartmental analyses in Phoenix 8.1 (Certara, Princeton, NJ). All mice that received the same dose for each strain were grouped as a single super mouse (n=24) during the population model development.
Results: A six-compartment model well described the PK of intraperitoneally administered cocaine and its two metabolites in plasma and brain (Figure 2, 3). There were no notable differences in the PK of cocaine or its metabolites across the six inbred strains studied (Figure 1). In the plasma, parent COC undergoes saturable metabolism to form NOR and BZE, which are distributed readily into the brain tissue. Simultaneously, these two metabolites are also formed in the brain, following a first-order rate formation. COC and NOR were shown to have mean Tmax of 0.13 ± 0.05h and 0.14 ± 0.04h, respectively while Tmax for BZE is beyond 60 min after IP cocaine injection.
Conclusion: The pharmacokinetics of cocaine and its metabolites were successfully characterized using a population-based PK model. Inter-strain variability in cocaine PK was reported in a previous study that also assessed several pharmacodynamic endpoints, including distance travelled, number of ambulatory movements, rearing behavior and average velocity. The lack of any PK or exposure differences seen across these six strains suggests that the known phenotypic differences in psychostimulatory response to cocaine could be driven by pharmacodynamic factors. Future studies will aim to model this difference between the six strains.
Daniel Weiner– Division of Pharmacotherapy, and Experimental Therapeutics, UNC Eshelman School of Pharmacy
Ryan Beechinor– Division of Pharmacotherapy, and Experimental Therapeutics, UNC Eshelman School of Pharmacy; UNC Hospitals and Clinics
Trey Thompson– Division of Pharmacotherapy, and Experimental Therapeutics, UNC Eshelman School of Pharmacy
Daniel Crona– Division of Pharmacotherapy, and Experimental Therapeutics, UNC Eshelman School of Pharmacy; Department of Pharmacy, UNC Hospitals and Clinics; UNC Lineberger Comprehensive Cancer Center
Lisa Tarantino– Division of Pharmacotherapy, and Experimental Therapeutics, UNC Eshelman School of Pharmacy; Department of Genetics, University of North Carolina at Chapel Hill