Cocaine and Metabolites Urinary Excretion after Controlled Smoked Administrationby M. A. Huestis, W. D. Darwin, E. Shimomura, S. A. Lalani, D. V. Trinidad, A. J. Jenkins, E. J. Cone, A. J. Jacobs, M. L. Smith, B. D. Paul

Journal of Analytical Toxicology

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Journal of Analytical Toxicology, Vol. 31, October 2007

Cocaine and Metabolites Urinary Excretion after

Controlled Smoked Administration*

Marilyn A. Huestis 1,*, W. David Darwin 1, Eric Shimomura 2, Shairose A. Lalani 2, Daniel V. Trinidad 2,

Amanda J. Jenkins 3, Edward J. Cone 4, Aaron J. Jacobs z,5, Michael L. Smith 2, and Buddha D. Paul 2

IChemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health,

Baltimore, Maryland; 2Division of Forensic Toxicology, Office of the Armed Forces Medical Examiner, Armed Forces Institute of

Pathology, Rockville, Maryland; 3Office of the Cuyahoga County Coroner, Cleveland, Ohio; 4johns Hopkins School of Medicine,

Baltimore, Maryland; and 5U.S. Army Medical Department Board, Fort Sam Houston, Texas

Abstract I

Understanding cocaine and metabolites urinary excretion following smoking is important for interpretation of urine test results in judicial, workplace and treatment settings. In National

Institute on Drug Abuse approved studies on a secure research unit, six subjects smoked placebo, 10, 20, and 40 mg cocaine with a precise dose delivery device and six different subjects smoked 42 mg cocaine in a glass pipe. Urine specimens (n -- 700) were collected for up to seven days and analyzed for cocaine (COC), benzoylecgonine (BE), ecgonine methylester (EME), m-hydroxybenzoylecgonine (mOHBE), p-hydroxybenzoylecgonine (pOHBE), norbenzoylecgonine (NBE), and ecgonine (EC) by gas chromatography-mass spectrometry. Results (mean _+ SE) for the 40-mg precise delivery doses are as follows:

COC BE EME mOHBE pOHBE NBE EC 10 20 10 25 25 25 50 Cutoff (ng/mL)

Cmax (ng/mL)

Tmax (h)

Last positive (h) 4085 9196 4638 222 540 614 852 _+ _+ _+ _+ + _+ + 2303 1569 1548 69 227 347 211 2.2 6.6 5.6 7.8 4.4 6.0 9.3 _+ _+ _+ _+ + _+ + 0.3 0.9 1.4 0.5 1.5 2.0 1.3 55 106 164 55 55 32 80

Mean Cma x for all analytes linearly increased with increasing dose.

Tma x was not dose-dependent. All metabolites were detected in some subjects within 2 h. EC concentrations were significantly * The opinions in this article are those of the authors and do not necessarily reflect the views of the Department of Army, Department of Air Force, Department of Defense or the National

Institute on Drug Abuse. * Author to whom correspondence should be addressed: Chemistry and Drug Metabolism,

Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 2t 224. E-mail: mhuestis@intra.nida.nih.gov. higher after smoked cocaine in a precise delivery coil compared to a glass "crack" pipe.

Introduction

Cocaine is the second most prevalent drug of abuse in the

United States and is a required analyte for the U.S. Substance

Abuse Mental Health Services Administration's (SAMHSA) federal workplace drug testing panel (1,2). Urine testing also is common for monitoring cocaine users in drug treatment and parole programs. Drug testing is expanding in Great Britain and Europe as cocaine consumption, a minor drug problem in the early 1990s, increases in frequency (3). Understanding cocaine metabolism and excretion is essential for the interpretation of cocaine urine test results.

The major metabolic routes for cocaine are well-documented (see Figure 1) (4). Three decades ago, Hamilton et al. (5) studied urinary excretion in six subjects who insufflated 1.5 mg/kg cocaine hydrochloride (105 mg for a 70 kg person).

CH 3 (OOll

OII

H

Ecgonine ( EC ) 4

CII 3

N r ~

It OC

O

Cocaine [C()C)

II ('H3 N ('OOH

N ('O(X'Ii 3

OH H OC

II

O

Ecgonine melhy] @sl~r (EME) []r (NBE) 4 (I13 ('H 3

N ('(•)H N ('iX)If ~" 0 ~* O

II O ( H O c OH

Benz~'lecgom ne (BE) p- H ) droxybcTizoylecgomllr (pOHBE) (H)

COOH N

I t 0 c 0 OH m-Hydroxyb~la~ I~goflinr (rnOHBEI

Figure 1. Metabolism of cocaine. 462 Reproduction (photocopying) of editorial content of this journal is prohibited without publisher's permission.

Journal of Anahtlical Toxicology, Vol. 31, October 2007

Peak urine cocaine concentrations of 300 to 24,000 ng/mL were reached in less than 1 h. Peak urine benzoylecgonine (BE) concentrations ranged from 8100 to 70,800 ng/mL with a time to reach maximum concentrations (Tmax)of 4 to 8 h.

Ambre et al. (6) later examined urine from five subjects following 4 h of intravenous infusion of cocaine hydrochloride with total doses ranging from 253 to 700 mg. As expected, peak cocaine and BE concentrations were higher than those of lower single doses, and interestingly, peak ecgonine methyl ester (EME) concentrations often exceeded those ofBE. Elimination half-lives of EME (2.3--4.1 h) and BE (2.8-6.5 h) were similar, but EME's was always shorter. In the last urine collections 24 h postdose, EME was always lower in concentration than BE.

Route of administration impacts the metabolic profile. Cone et al. (7) observed that cocaine was rapidly absorbed, metabolized, and excreted, and it was usually identified in the first urine void regardless of route of administration, including intravenous, intranasal, or smoking mutes. However, BE concentrations were route-dependent and represented 39%, 30%, and 16% of administered dose, respectively. After oral administration of multiple doses of cocaine hydrochloride (n = 6, 375-2000 mg each), peak urine concentrations for cocaine,

BE, and EME each exceeded 800,000 ng/mL for one subject (8).

Elimination occurred in two phases for all subjects. Alpha half-lives were similar to those previously reported, but beta phases were much longer. All of the past studies found great interindividual variation i absorption of cocaine nd limination of metabolites.

When one interprets urine drug tests, pharmacokinetic complexity is not the only difficulty. Most workplace, treatment, and judicial programs identify cocaine use by identifying BE in urine. Testing for this metabolite is required for federally regulated urine drug testing programs (1). Cocaine can be converted to BE in urine when the pH is basic, allowing the possibility of a positive t st due to external contamination (9).