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Author Topic: Bioavailability and Pharmacokinetics of Oral Cocaine in Humans  (Read 5514 times)

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Bioavailability and Pharmacokinetics of Oral Cocaine in Humans
« on: September 10, 2023, 01:15:25 PM »

Bioavailability and Pharmacokinetics of Oral Cocaine in Humans


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.


While cocaine is most commonly used by the smoked, intranasal and intravenous (IV) routes of administration, its oral use is widespread throughout South America. The coca leaves are chewed (either alone or with an activating alkaloid such as quinoa stalk ashes) and are used in various foods and beverages (e.g., cookies and teas). The few studies examining orally administered cocaine have demonstrated that orally and parenterally administered cocaine produce a qualitatively similar pharmacodynamic profile, including typical physiological and stimulant-like subjective effects, although the time-to-onset and peak effects are delayed after oral compared to parenteral administration.

Pharmacokinetic studies have shown that oral cocaine is absorbed well from the gastrointestinal tract, is detectable in plasma within 30 min of administration, and reaches peak plasma concentrations within 50–90 min. Estimates of oral cocaine bioavailability, ranging from 0.20 to 0.60, have been calculated only retrospectively by comparing data across different groups of subjects who received acute doses of either oral or IV cocaine. To date, there have been no prospective studies in humans designed to determine the oral bioavailability of cocaine. In the context of efforts to develop a human laboratory model to study cocaine abuse and withdrawal, a series of studies using orally administered cocaine was conducted that allowed examination of the pharmacokinetic profile of oral cocaine.

Cocaine is largely metabolized through four pathways: (i) liver carboxylesterase 1 (hCE1) hydrolyzes the methyl ester linkage of cocaine to form benzoylecgonine (BZE), (ii) intestinal carboxylesterase (hCE2) hydrolyzes the benzoate linkage to form ecgonine methyl ester (EME), (iii) serum butyrylcholinesterase (BchE) also produces EME (though with low catalytic efficiency)  and (iv) CYP450 3A4 demethylates cocaine to form norcocaine (NCOC). Further oxidative metabolism produces several minor hydroxy (e.g., m- and p-HOCOC; m- and p-HOBZE) metabolites. It has also been reported that cocaine can spontaneously hydrolyze in vitro at physiological temperature and pH to form BZE and EME at a rate of 4.8% total cocaine/h, though this observation has not been verified in vivo.

The metabolic disposition of oral cocaine administration has received little attention. A previous report indicated that repeated oral cocaine administration produced a metabolic profile that was unlike that observed after parenteral administration; however, these data were obtained after repeated cocaine administration, and it was unclear whether the differences in metabolism were due to the chronicity of dosing, the oral route of administration, or a combination of the two. After acute parenteral administration, plasma area-under-the-curve (AUC) for BZE has been estimated to range from 1- to 7-fold that of cocaine, but repeated oral administration resulted in BZE AUC values ~20-fold higher than cocaine. Likewise, EME AUCs after parenteral cocaine administration are three-fourths that of cocaine while EME AUCs after repeated oral administration were 5-fold higher than cocaine.

Under some circumstances, oral cocaine may be a useful route for human laboratory studies because (i) controlled dosing is easily achieved, (ii) the more gradual onset of effects, due to reduced systemic bioavailability and slower drug delivery to the brain and periphery, may present fewer medical risks than with parenteral administration and (iii) it obviates the exclusion of subjects with poor venous access and/or the need for approved smoking facilities. The present study is the first to characterize the bioavailability of oral cocaine prospectively and adds to the limited literature on the metabolic profile and pharmacokinetics of oral cocaine.

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