Bioavailability and Pharmacokinetics of Oral Cocaine in Humans

Abstract

The pharmacokinetic profile of oral cocaine has not been fully characterized and prospective data on oral bioavailability are limited. A within-subject study was performed to characterize the bioavailability and pharmacokinetics of oral cocaine. Fourteen healthy inpatient participants (six males) with current histories of cocaine use were administered two oral doses (100 and 200 mg) and one intravenous (IV) dose (40 mg) of cocaine during three separate dosing sessions. Plasma samples were collected for up to 24 h after dosing and analyzed for cocaine and metabolites by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis, and a two-factor model was used to assess for dose and sex differences. The mean ± SEM oral cocaine bioavailability was 0.32 ± 0.04 after 100 and 0.45 ± 0.06 after 200 mg oral cocaine. Volume of distribution (Vd) and clearance (CL) were both greatest after 100 mg oral (Vd = 4.2 L/kg; CL = 116.2 mL/[min kg]) compared to 200 mg oral (Vd = 2.9 L/kg; CL = 87.5 mL/[min kg]) and 40 mg IV (Vd = 1.3 L/kg; CL = 32.7 mL/[min kg]). Oral cocaine area-under-thecurve (AUC) and peak concentration increased in a dose-related manner. AUC metabolite-to-parent ratios of benzoylecgonine and ecgonine methyl ester were significantly higher after oral compared to IV administration and highest after the lower oral dose. In addition, minor metabolites were detected in higher concentrations after oral compared to IV cocaine. Oral cocaine produced a pharmacokinetic profile different from IV cocaine, which appears as a rightward and downward shift in the concentration-time profile. Cocaine bioavailability values were similar to previous estimates. Oral cocaine also produced a unique metabolic profile, with greater concentrations of major and minor metabolites.

Figure 1.

Mean ± SEM (N = 14) plasma cocaine concentrations for 24 h following administration of 100 and 200 mg oral cocaine (top panel) and 40 mg IV cocaine (bottom panel). Cocaine dosing occurred at time 0.

Figure 2.

Area-under-the-curve (AUC) oral 100 mg:IV 40 mg and oral 200 mg:IV 40 mg ratios for cocaine (COC) and major metabolites, benzoylecgonine (BZE) and ecgonine methyl ester (EME). AUC ratios for each oral/IV dose were calculated for each participant and averaged to determine dose-proportionality of cocaine and metabolite profile across the three dosing conditions. ^aAUCs for cocaine and metabolites after 40 mg IV cocaine = 1, ^bdose-adjusted AUC estimate for 100 mg dose = 2.5-fold higher than IV 40 mg dose, ^cdose-adjusted AUC estimate for 200-mg dose = 5-fold higher than IV 40 mg dose. Both Cocaine and BZE AUCs were lower than the dose-proportional estimated values. Cocaine AUCs were 0.8 and 2.1 for oral 100 and 200 mg relative to IV 40 mg, and BZE AUCs were 2- and 3.9-fold higher than the IV dose. EME AUCs after oral cocaine exceeded the dose-proportional estimated values, with AUCs after the 100 and 200 mg dose 5.6- and 10.9-fold higher than the IV dose.

Figure 3.

Mean ± SEM (N = 14) plasma benzoylecgonine (top panels) and ecgonine methyl ester (bottom panels) concentrations for 24 h after administration of 100 and 200 mg oral cocaine (left panels) and 40 mg IV cocaine (right panels). Cocaine dosing occurred at time 0.

Figure 4.

Maximum plasma concentration of cocaine (top), benzoylecgonine (BZE) (middle), and ecgonine methyl ester (EME) (bottom) for females (open bars) and males (solid bars). Top panel: There was a significant effect of sex for cocaine C_max [F(1,12) = 4.81, P = 0.049], but Tukey comparisons were non-significant when comparing females and males within each of the three dosing conditions, P > 0.05. While sex was not a significant factor, females also displayed higher C_max values than males for BZE (middle panel) and EME (bottom panel).