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Concurrent Pharmacokinetic Analysis of Plasma Cocaine and Adrenocorticotropic Hormone in Men¹

McLean Hospital/Harvard Medical School, Alcohol and Drug Abuse Research Center, McLean Hospital, Belmont, Massachusetts 02178

Address all correspondence and requests for reprints to: Jack H. Mendelson, M.D., Alcohol and Drug Abuse Research Center, McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02178.

	Abstract

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The purpose of this study was to determine the covariance between plasma cocaine and ACTH pharmacokinetics. Twelve healthy male occasional cocaine users participated in a double blind study. Intravenous cocaine (0.2 mg/kg) or placebo was infused over 1 min, and samples for cocaine, ACTH and cortisol analysis were collected at 2, 4, 8, 12, 16, 20, 30, 40, 60, 80, 120, 180, and 240 min. Peak cocaine plasma levels averaged 101.2 ± 14.6 ng/mL. ACTH increases were significantly correlated (P < 0.0001) with increases in plasma cocaine levels (r = 0.67; r² = 0.44). Pharmacokinetic analysis showed that the t_max (observed time to maximum concentration) values for cocaine (6.0 ± 1.4 min) and ACTH (7.3 ± 1.2 min) were almost identical. The area under the curve was calculated using the trapezoidal rule. The area under the curve for plasma cocaine was 6463 ± 1070 ng/min·mL, and the area under the curve for ACTH was 1873 ± 188 pmol/min·L. The mean half-life for plasma cocaine was 46.7 ± 4.0 min, and that for ACTH was 35.8 ± 5.1 min. Cardiovascular and subjective effect measures were correlated with concurrent increases in plasma cocaine and ACTH levels.

	Introduction

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IT HAS BEEN postulated that cocaine’s effects on corticotropin-releasing factor (CRF) may be one mechanism underlying the reinforcing properties of cocaine in experimental animals and humans (1, 2, 3, 4, 5, 6, 7, 8, 9, 10). Cocaine-stimulated ACTH and corticosterone secretions in rodents were completely blocked by peripheral and intracerebroventricular administration of both CRF antiserum and a CRF receptor antagonist (7, 11). In vivo studies revealed that cocaine alters the immunoreactive CRF levels in the hypothalamus and in several extrahypothalamic-limbic brain regions (8). Mendelson et al. (4, 5) reported that acute cocaine (30 mg) administration significantly increased plasma ACTH levels within 5 min of iv injection in cocaine-dependent men. The goal of this study was to determine the covariance between plasma cocaine levels and ACTH in occasional cocaine users.

	Experimental Subjects

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Twelve healthy adult men between the ages of 21–35 yr provided written informed consent for participation in studies to determine the acute effects of cocaine on behavioral, cardiovascular, and neuroendocrine function. Informed consent was based upon approval and review of the study by the McLean Hospital institutional review board. All subjects reported occasional cocaine inhalation or insufflation on four to eight occasions during the year before the study. All men were in good physical health, and all had normal medical and laboratory screening examinations and no history of psychiatric problems or drug or alcohol abuse. There were no statistically significant differences between the two groups with respect to weight, height, and body mass index. Subjects were screened for drug use just before each study began using Triage urine screening kits (Biosite Diagnostics, San Diego, CA), and all urine specimens were negative for licit and illicit drugs. The characteristics of the subjects are summarized in Table 1.

	Materials and Methods

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Blood samples for the determination of plasma cocaine, cortisol, and ACTH analysis were collected at baseline and 2, 4, 8, 12, 16, 20, 30, 40, 60, 80, 120, 180, and 240 min after iv administration. All blood samples for cocaine, cortisol, and ACTH determinations were obtained with a Kowarski-Cormed thrombo-resistant blood withdrawal butterfly needle and tubing set (Dakmed Inc., Buffalo, NY) inserted into the arm opposite that from which cocaine was iv injected. Samples were immediately centrifuged, and plasma was removed and frozen at -70 C for cocaine, ACTH, and cortisol analyses. Subjects were asked to report their perception of drug intensity (high), euphoria, good effects, bad effects, and cocaine craving 5 min after completion of iv cocaine or placebo administration. Measurements of heart rate and systolic and diastolic blood pressure were carried out in all subjects before iv cocaine injection and 1, 3, 6, 9, 12, 15, 18, and 21 min after injection.

Cocaine hydrochloride and placebo preparation

Cocaine hydrochloride was acquired from the NIDA in powder form and was dissolved in sterile water for iv injection. Sterility was ensured by passing the solution through a 0.22-µm Millipore filter (Millipore Corp., Bedford, MA) and subjecting it to a Limulus amebocyte lysate test for detection of Gram-negative bacterial endotoxins. The test kit is manufactured by BioWhittaker (Walkersville, MD). A commercial preparation of 0.9% saline (1 mL) in sterile vials was used as the placebo challenge.

ACTH RIA procedures

Plasma ACTH concentrations were measured in duplicate using an immunoradiometric assay kit purchased from Corning Nichols Institute (San Juan Capistrano, CA). The assay sensitivity was 0.2 pmol/L, and the intra- and interassay coefficients of variance were 3.5% and 11.0%, respectively.

Cortisol RIA procedures

Plasma cortisol concentrations were measured in duplicate by the GammaCoat RIA method using kits purchased from Incstar Corp. (Stillwater, MN). The assay sensitivity was 0.1 µg/dL, and the intra- and interassay coefficients of variance were 3.2% and 6.3%, respectively.

Plasma cocaine analysis

Plasma cocaine levels were measured in duplicate using a solid phase extraction method described in the SPEC Instruction Manual by Ansys with a Hewlett-Packard model 5890 Series II gas chromatograph equipped with a capillary column and a Hewlett-Packard 5971 Series Mass Selection detector (Hewlett-Packard, Palo Alto, CA) (12). The assay sensitivity was 10 ng/mL, and intra- and interassay coefficients of variance were 2.5% and 4.4%, respectively.

Data analysis

Plasma ACTH, cocaine, and cortisol values for subjects were analyzed using a 2 (group) x 15 (time) repeated measures ANOVA. Heart rate and systolic and diastolic pressure were analyzed using a 2 (group) x 8 (time) repeated measures ANOVA. If significant main effects were detected, one-way ANOVAs were performed to identify the times at which groups significantly differed. Subjective behavioral responses were analyzed with a one-way ANOVA. Correlations between ACTH and plasma cocaine levels were determined by regression analysis. Cocaine pharmacokinetics were carried out with a pharmacological calculation system based upon the Manual of Pharmacologic Calculations with Computer Programs (13) using PHARM/PCS Version 4.2 (MicroComputer Specialists MCS, Philadelphia, PA). The area under the curve was calculated using the trapezoidal rule.

	Results

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The increases in plasma ACTH were significantly correlated (P < 0.0001) with increases in plasma cocaine levels (r = 0.67; r² = 0.44). After 0.2 mg/kg iv cocaine administration, ACTH increased significantly (P < 0.05) from baseline 4 min after iv injection and persisted for 30 min. ACTH peaked 8 min after iv cocaine administration. There was no significant change in ACTH levels after placebo iv administration. Plasma cortisol levels were significantly increased (P < 0.05) at 16 min, and peak levels occurred at 30 min after 0.2 mg/kg iv cocaine administration and remained significantly elevated until 40 min. There was no change in cortisol levels after placebo injection (Fig. 1).

View larger version (27K): [in this window] [in a new window]   Figure 1. Plasma cocaine ACTH and cortisol levels after cocaine and placebo injections.

	Discussion

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The rapid increase in plasma ACTH levels after iv cocaine administration was significantly correlated with plasma cocaine levels (P < 0.0001). Pharmacokinetic analysis revealed that the t_max of plasma ACTH and cocaine levels after iv injection of 0.2 mg/kg cocaine occurred at 7.3 ± 1.2 and 6.0 ± 1.4 min, respectively. Significant cocaine effects for induction of euphoria were observed 5 min after iv cocaine administration. Behavioral and neuroendocrine responses after iv cocaine administration were paralleled by significant changes in heart rate. Both plasma cocaine levels and ACTH levels rapidly decreased after peak values shortly after iv cocaine. Pharmacokinetic analysis revealed that the cocaine t_1/2 of 46 min was very similar to the value of 48 min reported by Chow et al. (14).

The stimulatory effects of cocaine on pulsatile ACTH secretion in rodents are mediated in part by CRF, as cocaine-induced increases in ACTH release from the pituitary are prevented by passive immunization of CRF (7, 11). In addition, pretreatment with a CRF receptor antagonist inhibited cocaine-induced increases in corticosteroids in rodents (11). In vitro studies have revealed that cocaine stimulates CRF release from hypothalamic tissue (2), but had no effect on ACTH secretion from isolated pituitary cells (7). It has also been reported that acute cocaine administration increased levels of CRF messenger ribonucleic acid in the paraventricular nucleus of the hypothalamus (15). In addition, bilateral lesions of the paraventricular nuclei suppressed cocaine stimulation of ACTH release (15).

Cocaine blocks the reuptake of dopamine, serotonin, and norepinephrine (16). Both dopamine and serotonin are involved in the modulation of cocaine-induced ACTH and corticosteroid release (1, 3). We have previously postulated (9) that cocaine’s rapid induction of pulsatile ACTH release may reflect cocaine-induced CRF stimulation as a consequence of cocaine’s effects on monoaminergic transmitter systems in brain. There are multiple CRF systems throughout the central nervous system in addition to CRF in the basal hypothalamus that stimulates ACTH release. Therefore, rapid CRF activation in brain by cocaine may be one important mechanism in the induction and perpetuation of cocaine abuse and dependence. At present, no safe and effective medications are available for the treatment of cocaine abuse and dependence (17). Development of new pharmacotherapies based upon cocaine’s effects on CRF and ACTH secretory processes may facilitate improved treatment for cocaine abuse and dependence.

	Acknowledgments

 
The administrative and editorial assistance of Rita Head and Eleanor DeRubeis, and the technical assistance of Alexandra Richman, Jodi Avery, J. Wallis Sholar, Yong Hong Cheng, Howard Gelles, and Alicja Skupny are gratefully acknowledged.

	Footnotes

 
¹ This work was supported in part by Grants DA-04059, DA-09448, DA-00101, and DA-00064 from the NIDA, NIH, and the Dr. Ralph and Marian C. Falk Medical Research Trust.

Received October 2, 1997.

Revised November 7, 1997.

Accepted November 17, 1997.

	References

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