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PubMed2005

The quantitative analysis of heroin, methadone and their metabolites and the simultaneous detection of cocaine, acetylcodeine and their metabolites in human plasma by high-performance liquid chromatography coupled with tandem mass spectrometry.

For a pharmacokinetic-pharmacodynamic study in opioid tolerant patients, who were treated with heroin in combination with methadone, a liquid chromatographic assay with tandem mass spectrometry detection (LC-MS/MS) was developed for the simultaneous determination of heroin, methadone, heroin metabolites 6-monoacetylmorphine, morphine, and morphine-6 and 3-glucuronide and methadone metabolite EMDP. To detect any abuse of substances besides the prescribed opioids the assay was extended with the detection of cocaine, its metabolites benzoylecgonine and norcocaine and illicit heroin adulterants acetylcodeine and codeine. Heroin-d6, morphine-d3, morphine-3-glucuronide-d3 and methadone-d9 were used as internal standards. The sample pre-treatment consisted of solid phase extraction using mixed mode sorbent columns (MCX Oasis). Chromatographic separation was performed at 25 degrees C on a reversed phase Zorbax column with a gradient mobile phase consisting of ammonium formate (pH 4.0) and acetonitrile. The run time was 15 min. MS with relatively mild electrospray ionisation under atmospheric pressure was applied. The triple quadrupole MS was operating in the positive ion mode and multiple reaction monitoring (MRM) was used for drug quantification. The method was validated over a concentration range of 5-500 ng/mL for all analytes. The total recovery of heroin varied between 86 and 96% and of the heroin metabolites between 76 and 101%. Intra-assay and inter-assay accuracy and precision of all analytes were always within the designated limits (< or =20% at lower limit of quantification (LLQ) and < or =15% for other samples). This specific and sensitive assay was successfully applied in pharmacokinetic studies with medically prescribed heroin and toxicological cases.

Administration, Inhalation↗
PubMed2004

Emerging patterns of cannabis and other substance use in Aboriginal communities in Arnhem Land, Northern Territory: a study of two communities.

A recent rise in cannabis use in Indigenous communities in northern Australia may have compounded existing patterns of other substance use. This paper describes these patterns in Arnhem Land in the 'Top End' of the Northern Territory (NT). Economic impacts of the cannabis trade are also described. In a descriptive cross-sectional study, random samples included 336 people (169 males, 167 females) aged 13 - 36 years. Consensus classification of lifetime and current use of cannabis, alcohol, tobacco, kava, inhalants (petrol) and other drugs was derived based on health workers' proxy assessments. A sample (n = 180, aged 13 - 36) was recruited opportunistically for interview. Lifetime cannabis users among those interviewed (n = 131, 81 males, 50 females) described their current cannabis use, usual quantities purchased and consumed, frequency and duration of cannabis use and other substance use. In the random samples, 69% (63 - 75%) of males and 26% (20 - 31%) of females were lifetime cannabis users (OR = 7.4, 4.5 - 12.1, p < 0.001). The proportion of males currently using cannabis was 67% (60 - 73%) while the proportion of females currently using cannabis was 22% (16 - 27%) (OR = 7.9, 4.8 - 13.1, p < 0.001). Current cannabis users were more likely than non-users to be also using alcohol (OR = 10.4, 4.7 - 23.3, p < 0.001), tobacco (OR = 19.0, 7.9 - 45.8, p < 0.001) and to have sniffed petrol (OR = 9.1, 4.6 - 18.0, p < 0.001) but were less likely to be using kava (OR = 0.4, 0.2 - 0.9, p < 0.001). Among those interviewed, higher tobacco consumption in current users and greater alcohol use in lifetime users was associated with increased cannabis use. Action is required to reduce cannabis use, especially in combination with other substances.

Adolescent↗
PubMed2005

Interpretation of analytical toxicology results in life and at postmortem.

Interpretation of analytical toxicology results from live patients is sometimes difficult. Possible factors may be related to: (i) the nature of the poison(s) present; (ii) sample collection, transport and storage; (iii) the analytical methodology used; (iv) the circumstances of exposure; (v) mechanical factors such as trauma or inhalation of stomach contents; and (vi) pharmacological factors such as tolerance or synergy. In some circumstances, detection of a drug or other poison may suffice to prove exposure. At the other extreme, the interpretation of individual measurements may be simplified by regulation. Examples here include whole blood alcohol (ethanol) in regard to driving a motor vehicle and blood lead assays performed to assess occupational exposure. With pharmaceuticals, the plasma or serum concentrations of drugs and metabolites attained during treatment often provide a basis for the interpretation of quantitative measurements. With illicit drugs, comparative information from casework may be all that is available. Postmortem toxicology is an especially complex area since changes in the composition of fluids such as blood depending on the site of collection from the body and the time elapsed since death, amongst other factors, may influence the result obtained. This review presents information to assist in the interpretation of analytical results, especially regarding postmortem toxicology. Collection and analysis of not only peripheral blood, but also other fluids/tissues is usually important in postmortem work. Alcohol, for example, can be either lost from, or produced in, blood especially if there has been significant trauma, hence measurements in urine or vitreous humour are needed to confirm the reliability of a blood result. Measurement of metabolites may also be valuable in individual cases.

Chemistry Techniques, Analytical↗
PubMed1998

Cocaine metabolism and urinary excretion after different routes of administration.

Cocaine abusers frequently self-administer cocaine by different routes of administration. A controlled-dosing study was performed to assess the effect of different routes of administration on the excretion profile of cocaine and metabolites in urine. Single bioequivalent doses of cocaine were administered by the intravenous, intranasal, and smoked routes to six human subjects. Urine specimens were collected for 3 days after drug administration and were analyzed for cocaine, metabolites, and anhydroecgonine methyl ester, the thermal degradation product of cocaine, by gas chromatography-mass spectrometry. Cocaine was rapidly absorbed, metabolized, and excreted in urine. Peak cocaine concentrations were generally present in the first specimen collected; thereafter, concentrations declined quickly and were usually below the limit of detection (approximately 1 ng/ml) within 24 hours. The metabolite benzoylecgonine was present in the highest concentration and represented approximately 39%, 30%, and 16%, of the administered dose by the intravenous, intranasal, and smoked routes, respectively. Combined amounts of ecgonine methyl ester and six minor metabolites (norcocaine, benzoylnorecgonine, m-hydroxycocaine, p-hydroxycocaine, m-hydroxybenzoylecgonine, and p-hydroxybenzoylecgonine) accounted for approximately 18%, 15%, and 8% of the administered dose by the intravenous, intranasal, and smoked routes, respectively. Anhydroecgonine methyl ester was present in trace amounts (0.02% dose) in specimens collected after smoked cocaine administration. Because many of these metabolites exhibit pharmacologic activity, their presence in urine may indicate that they play complex biologic roles in the overall activity of cocaine.

Administration, Inhalation↗
PubMed2005

[Absence of correlation between mental disorders and high-dose buprenorphine. A case-control study].

BACKGROUND: In France today, the treatment of opiate and notably heroin addiction with high-dose buprenorphine (HDB) is widespread. Although this treatment has been successful to some extent, problems persist. One is that some percentage (estimated at 17-47%) of patients "misuses" their HDB, either by intravenous injection or inhalation. This misuse presents a public health problem, since injecting drug users are more frequently infected by hepatitis C, and may even jeopardize the treatment's efficacy. METHOD: Our study compared a sample of 26 patients treated with sublingual HDB who reported injecting it on occasion and 27 patients under HDB who did not inject it. RESULTS: There was no evidence of more psychiatric disorders in the population that injected HDB than in the population that did not. Conversely, the patients injecting HDB used more illicit products, more benzodiazepines and more alcohol. DISCUSSION: Despite its efficacy, substitution treatment does not appear to provide relief for some patients. HDB injection may thus correspond to a search for a precarious balance: the disruption of the HDB kinetics induced by its injection would be aimed at enhancing the opiate effect. The consumption of other licit and illicit psychotropic agents indicates a further attempt to obtain relief from a persistent mental discomfort, over and above the substitution therapy and even its misuse. The reality of the psychological imbalance experienced with, induced by or pre-existing the heroin use requires rethinking the overall treatment. Future studies should lead to the identification of the disorders that lead these patients to seek relief in injections.

Administration, Sublingual↗
PubMed2002

Prevalence and genotypes of hepatitis C virus infection among drug addicts and blood donors in Thailand.

Hepatitis C virus (HCV) is an infectious agent that has the potential to cause chronic liver disease, cirrhosis and hepatocellular carcinoma. We determined the prevalence and genotypes of HCV infection among groups of drug addicts: intravenous drug users (n = 134), methamphetamine users (n = 100), inhaled-drugs users (n = 19) and alcoholics (n = 50); a group of blood donors acted as a control. The control group consisted of 179 randomly-selected anti-HCV positive samples: these were subjected to HCV RNA screening and genotyping. The anti-HCV test was performed by ELISA: HCV RNA screening was by nested RT-PCR that employed primers from the 5' noncoding region. The genotype assay was based upon analysis of the 5' NCR amplified sequences and RFLP. Hepatitis C virus was highly prevalent among all groups of drug addicts (12-70%). In 2000. among the new blood donors (n = 66,340) at the National Blood Center, Thai Red Cross, anti-HCV prevalence amounted to 0.98%. The HCV genotype distribution showed that the most prevalent genotype was 3a, followed by 1b and 6a. Our data demonstrated the very high prevalence of HCV infection in IVDUs, a finding that is consistent with the blood-borne nature of the virus. In order to curb HCV infection, a determined effort to educate both the general population and high-risk groups is required; such a program of education would address both general and particular methods of transmission, especially the use of non-sterile needles etc.

Alcoholism↗
PubMed2005

Quantitative and isomeric determination of amphetamine and methamphetamine from urine using a nonprotic elution solvent and R(-)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid chloride derivatization.

Forensic Urine Drug Testing Laboratories often requires two confirmatory methods for a methamphetamine positive screen. First, methamphetamine is identified and quantitated using gas chromatography-mass spectrometry. If the total methamphetamine concentration is above the administrative cutoff level, the isomeric composition must be determined. This eliminates a possible contribution by over-the-counter cold medications that contain l-methamphetamine (Vick's inhalers). Products that contain only the l-isomer of methamphetamine must be distinguishable from prescription or illicitly manufactured methamphetamine, which consists mainly of the d-isomer. Optically impure derivatizing reagents will produce an impure mixture from a pure isomeric compound. Therefore, methods utilizing impure reagents can prove problematic when interpreting results. Use of an optically pure chiral derivatizing reagent, such as R(-)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid chloride, allows for the creation and measurement of chromatographically separable isomeric compounds. The novel method described here utilizes a polymer-based solid-phase column adapted to a positive pressure manifold extraction system and a one-step derivatization process that occurs directly in the elution solvent. This methodology eliminates an elution solvent dry-down step that may adversely affect recovery of volatile amphetamine compounds. Although the method was designed for the quantitative analysis of the isomers of amphetamine and methamphetamine, it can be adapted for use with a wide range of phenethylamines including methylenedioxyamphetamine, N-methylenedioxymethamphetamine, and possibly N-methylenedioxyethylamphetamine. The linear range for quantitation was 25-10,000 ng/mL for d,l-methamphetamine and d,l-amphetamine, and correlation coefficients were 0.997 or better. The coefficient of variation for all four analytes did not exceed 2.8%. Concentrations analyzed ranged from 500 to 4000 ng/mL (n=40). The method allows for a simple and accurate quantitation and isomeric determination of amphetamine and methamphetamine using a process that eliminates extraction and derivatization complications common in current methods.

Amphetamine↗
PubMed1998

Effects of the abused solvent toluene on recombinant N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors expressed in Xenopus oocytes.

Previous studies have shown that toluene, which is commonly abused, depresses neuronal activity and causes behavioral effects in both animals and man similar to those observed for ethanol. In this study, the oocyte expression system was used to test the hypothesis that toluene, like ethanol, inhibits the function of ionotropic glutamate receptors. Oocytes were injected with mRNA for specific N-methyl-D-aspartate (NMDA) or non-NMDA subunits and currents were recorded using conventional two-electrode voltage clamp. To enhance the low water solubility of toluene, drug solutions were prepared by mixing toluene with alkamuls (ethoxylated castor oil) at a 1:1 ratio (v:v) and diluting this mixture to the appropriate concentration with barium-containing normal frog Ringer solution. Alkamuls, up to 0.1%, had no significant effects on membrane leak currents or on NMDA-induced currents. Toluene, up to approximately 9 mM, had only minor effects on membrane leak currents but dose-dependently inhibited NMDA-mediated currents in oocytes. The inhibition of NMDA receptor currents by toluene was rapid, reversible and the potency for toluene's effects was subunit dependent. The NR1/2B subunit combination was the most sensitive with an IC50 value for toluene-induced inhibition of 0.17 mM. The NR1/2A and NR1/2C receptors were 6- and 12-fold less sensitive with IC50 values of 1.4 and 2.1 mM, respectively. In contrast, toluene up to approximately 9 mM did not inhibit kainate-induced currents in oocytes expressing GluR1, GluR1(+)R2 or GluR6 subunits. These results suggest that some of the effects of toluene on neuronal activity and behavior may be mediated by inhibition of NMDA receptors.

Anesthetics, Inhalation↗
PubMed2005

Fentanyl and its analogues in clinical and forensic toxicology.

Fentanyl and its analogues are commonly named synthetic opiates. Some compounds from fentanyl group (e.g. fentanyl, alfentanil, sufentanil, remifentanil) are used as anaesthetic and analgesic of high potency and short duration of action. Effects of acting fentanyls are indistinguishable from those produced by nasal inhalation of street heroin. In view of this, fentanyls are very "attractive" for the narcotic market. In least years an increase in number of reports about illegal production and non-medical use of fentanyl and its analogues have appeared. Numerous fentanyl analogues are sold under one name synthetic heroine or China white. Fentanyl and its analogues also can be used as gas warfare agents. One of fentanyl-related compound was used during action of easing hostages from Dubrovka theatre. Because of respiratory depression, which was caused by used compound, died over 100 hostages. Because of high potency fentanyl-related compounds are used in very low doses. So fentanyls appear in biological material in very low concentrations, not higher than several nanograms per millilitre or per gram. The drugs in these concentrations cannot be detected by means of routinely used screening procedures. Therefore direct methods for determination of this group of compounds are needed. Screening method for determination of fentanyl and its analogues was elaborated and validated. Liquid chromatography-mass spectrometry (LC/MS) technique was applied. The method is characterised by the limit of quantification (LOQ) and the limit of detection (LOD) ranged from 0.6 to 2 ng/ml and from 0.2 to 0.6 ng/ml, respectively for four above-mentioned compounds. The method was used for determination of fentanyl in three forensic cases. The blood, bile and blood from lung samples were taken during autopsy of persons who died shortly after surgical procedure in which fentanyl was used as an adjunct to general anaesthesia.

Analgesics, Opioid↗
PubMed1996

Cocaine toxicity and isoflurane anesthesia: hemodynamic, myocardial metabolic, and regional blood flow effects in swine.

OBJECTIVES: Increasing numbers of people use cocaine recreationally and may require anesthesia care, having recently abused the drug. However, no data currently exist concerning potential interactions between toxic levels of cocaine and volatile anesthetic agents. This study investigated the effects of cocaine infusion on systemic hemodynamics, myocardial metabolism, and regional organ blood flow in relation to depth of isoflurane anesthesia. DESIGN: Prospective, randomized, controlled trial. SETTING: A laboratory at a university medical center. PARTICIPANTS: Twelve miniature pigs. INTERVENTIONS: An open-chest swine model was used. Isoflurane (ISO) was the sole anesthetic, administered at 0.75 and 1.5 minimum alveolar concentration (MAC), and cocaine was infused (n = 6) at a rate of 0.5 mg/kg/min. Control animals (n = 6) received an equivalent amount of normal saline. MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary arterial pressures and thermodilution cardiac output data were collected at 0.75 MAC and 1.5 MAC ISC. Regional myocardial and blood flows to other organs were measured using radiolabeled microspheres. Arrhythmias and altered ventricular conduction were noted only in the cocaine group, along with significant elevations in diastolic arterial pressure, coronary perfusion pressure, and systemic vascular resistance. Increased subendocardial blood flow occurred during cocaine infusion (p = 0.03); subepicardial perfusion was unchanged. Cerebral (p < 0.01) and spinal cord (p < 0.05) blood flows were reduced in animals receiving cocaine. Other organ blood flows were unchanged with depth of anesthesia or cocaine administration, with the exception of splenic blood flow (p < 0.04). CONCLUSIONS: Moderately toxic cocaine levels occurring during isoflurane at 0.75 MAC and 1.5 MAC are associated with hemodynamic abnormalities, a marked increase in systemic vascular resistance, and a tendency to produce cardiac arrhythmias. A reversal of endo/epicardial myocardial perfusion ratio occurs associated with cocaine infusion during ISO anesthesia. This is probably not related to a primary redistribution of subendocardial blood flow and may be related to a combination of increased myocardial oxygen demand and epicardial coronary vasoconstriction. The reductions in cerebral and spinal cord perfusion observed may explain, in part, the neurologic sequelae of cocaine toxicity.

Anesthetics, Inhalation↗
PubMed1994

Pharmacokinetics and pharmacodynamics of smoked heroin.

Despite the current popularity of smoking as a route of drug self-administration, there have been few human studies characterizing the pharmacokinetics and pharmacodynamics of smoked drugs of abuse. A variety of technological difficulties are encountered in the design of smoking studies, such as delivering reproducible doses and limiting the amount of pyrolysis of parent drug. As part of a concerted research effort to deliver precise, smoked doses of drug, a computer-assisted smoking device was utilized that delivered single puffs of heroin vapor to human subjects under controlled clinical conditions. Recovery studies indicated that the smoking device delivered approximately 89% of parent heroin to subjects. Although only two qualified heroin smokers could be identified as eligible volunteers, their participation provided the unique opportunity to study the pharmacokinetics and pharmacodynamics of smoked heroin. The two subjects were administered four smoked heroin doses in ascending order. In addition, four intravenous doses of heroin were administered for comparison of effects and estimation of bioavailability. Concurrent physiological, behavioral, and performance measures were collected along with blood samples. Blood was analyzed for heroin, 6-acetylmorphine, and morphine by solid-phase extraction gas chromatography-mass spectrometry. Heroin appeared rapidly in blood after administration and peaked 1-5 minutes after smoking, which is similar to that observed following intravenous administration. Heroin concentrations declined rapidly to the limit of detection (1.0 ng/mL) by 30 minutes. 6-Acetylmorphine blood concentrations also peaked and declined rapidly after smoked heroin with peak concentrations occurring at 1-2 minutes after smoking. Morphine levels rose and decayed more slowly. Mean elimination half-lives for heroin, 6-acetylmorphine, and morphine were 3.3 min, 5.4 min, and 18.8 min, respectively, by the smoked route. The bioavailability of smoked heroin was highly variable. Physiological measures such as pupil diameter demonstrated a counterclockwise hysteresis compared with heroin blood levels. The rapid onset of pharmacological effects together with the early appearance of heroin and metabolites in blood following smoked heroin demonstrated the effectiveness of this route of drug administration. It is evident that the smoking route enables individuals to obtain similar pharmacological effects as are produced by intravenous administration of heroin.

Administration, Inhalation↗
PubMed2004

Enantiomeric separation and quantitation of (+/-)-amphetamine, (+/-)-methamphetamine, (+/-)-MDA, (+/-)-MDMA, and (+/-)-MDEA in urine specimens by GC-EI-MS after derivatization with (R)-(-)- or (S)-(+)-alpha-methoxy-alpha-(trifluoromethy)phenylacetyl chloride (MTPA).

In drug testing, the presence of methamphetamine in urine is generally confirmed by a gas chromatography-mass spectrometry (GC-MS) method. Derivatization of the compound to a perfluoroalkylamide, prior to confirmation, typically yields better chromatographic separation. Once methamphetamine is detected, a second GC-MS test is necessary to distinguish positive results from the use of over-the-counter medication, Vicks inhaler, or from use of a prescription drug, selegiline (Deprenyl). R-(-)-Methamphetamine is the urinary product from legitimate use of these medications. The second GC-MS test is to confirm illicit use of (S)-(+)-methamphetamine. In the procedure, the two methamphetamine isomers are changed to the chromatographically separable diastereomers by a chiral derivatizing agent, (S)-(-)-trifluoroacetylprolyl chloride (TPC). But the method has inherent limitations. Racemization of the reagent produces mixed diastereomers even from pure (S)-(+)-methamphetamine. Instead of using TPC, we utilized (R)-(-)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride (MTPA) to prepare the amides of diastereomers of methamphetamine. No racemization was observed with this reagent. The method was extended to resolve GC peaks of (R)-(-)- and (S)-(+)-isomers of amphetamine, 3,4-methylenedioxyamphetamine (MDA), N-methyl-MDA (MDMA), and N-ethyl-MDA (MDEA). Three ions from the drug and two ions from the deuterated internal standard were monitored to characterize and quantitate the drugs. For MDEA, only one ion was used. The quantitation was linear over 25 to 5000 ng/mL for MDEA and 25 to 10,000 ng/mL for all other drugs. Correlation coefficients were > 0.996. Precision calculated as the coefficient of variation at the calibrator concentration of 500 ng/mL was within +/- 11% for all drugs. The method was applied to test 43 urine specimens. In 91% of the methamphetamine-positive specimens, only the (S)-(+)-isomer was detected. In all MDMA-positive specimens, the concentrations of (R)-(-)-isomer were greater than the (S)-(+)-isomer indicating longer retention of (R)-(-)-isomer in the human body. The specimen concentrations (R + S) compared well with that of a non-chiral method that used 4-carboethoxyhexafluorobutyryl chloride as derivatizing agent. But the MTPA method has some advantage. It alone can replace the two GC-MS methods needed to confirm the presence of (S)-(+)-isomers of amphetamine and methamphetamine.

3,4-Methylenedioxyamphetamine↗
PubMed1995

Comparison of heroin and cocaine concentrations in saliva with concentrations in blood and plasma.

Saliva is an alternate biological matrix for drug testing that has several advantages over more traditional fluids such as blood and urine. Collection is rapid, noninvasive, and relatively easy to obtain. Several reports have detailed the appearance of drugs of abuse in saliva, but few have compared the excretion profiles of drugs administered by different routes. In this study, subjects were administered three smoked and three intravenous doses of heroin in an ascending dose design. Blood and saliva were collected periodically after drug administration and analyzed by gas chromatography-mass spectrometry (GC-MS) for heroin, 6-acetylmorphine, and morphine. In a second study, subjects were administered a single, smoked dose of 40 mg cocaine base and an intravenous dose of 44.8 mg cocaine HO on separate occasions. Plasma and saliva were collected and analyzed by CC-MS for cocaine, anhydroecgonine methyl ester (AEME), and seven additional metabolites. Heroin and 6-acetylmorphine were detected in the first saliva sample collected (2 min) following drug administration by both routes. Peak heroin concentrations were achieved quickly, between 2 and 5 min after intravenous administration and at 2 min after smoke heroin. Peak heroin concentrations in saliva after smoking heroin base ranged from 3534 (2.6 mg) to 20,580 ng/mL (5.2 mg), and after intravenous administration, concentrations ranged from 6 (10 mg heroin HCl to 30 ng/mL (12 mg heroin HCl. Saliva concentrations of heroin declined rapidly after intravenous administration, reaching the limit of sensitivity of the assay (1 ng/mL) by 60 min. Heroin concentrations in saliva after smoking declined slowly; detection times ranged from 4 to 24 h. Cocaine was the major analyte detected in saliva and plasma after smoked and intravenous administration. Peak saliva cocaine concentrations after intravenous administration ranged from 428 to 1927 ng/mL (N = 7); after smoking, they ranged from 15,852 to 504,880 ng/mL (N = 7). Peak plasma cocaine concentrations after intravenous administration ranged from 122 to 442 ng/mL A = 7), and after smoking, concentrations ranged from 46 to 291 ng/mL A = 7). The thermal degradation product of cocaine, AEME, was detected in saliva but not in plasma after smoking. Peak saliva AEME concentrations were achieved at 2 min and ranged from 558 to 4374 ng/mL (N = 7). These are the first reported observations of heroin and metabolites in saliva following heroin smoking and of AEME in saliva after smoking cocaine base. The presence of AEME in saliva may be useful as a marker of the smoked route following cocaine administration.

Administration, Inhalation↗
PubMed2001

Urinary excretion profiles for total morphine, free morphine, and 6-acetylmorphine following smoked and intravenous heroin.

Heroin is one of the major target drugs in workplace drug-testing programs because of its history of abuse, liability, and continued negative social impact. This study was a comprehensive examination of pharmacokinetics, pharmacodynamics, detection times, opiate immunoassay performance, and urine excretion profiles following single doses of heroin administered to human subjects via smoking and intravenous routes. Studies of the first four components of this investigation were previously published. This article describes the urine excretion profiles. Total morphine (Tmor), free morphine (Fmor), and 6-acetylmorphine (6-AM) were measured by gas chromatography-mass spectrometry (GC-MS) in 920 urine samples collected from 11 male human subjects following single doses of heroin. Eight received intravenous doses of 3, 6, and 12 mg heroin HCI and four smoked 3.5-, 5.2-, 7-, 10.5-, or 13.9-mg doses of heroin (base). In addition, 183 urine-based blind quality-control samples were added to the study set to assess assay performance. Creatinine was also measured in each sample by a colorimetric technique. The parameters studied were not significantly dependent on route of administration. Excretion half-life mean +/- SD for Tmor was 3.11 +/- 0.30 h. Range (median) of peak urine concentrations, time to peak, time to last positive sample for low cutoff (300 ng/mL) and high cutoff (2000 ng/mL) for Tmor following lower doses (< or = 7 mg) were, respectively, 1392-9250 (3620) ng/mL, 1.2-6.2 (2.3) h, 7.4-31.9 (7.4) h, and 0-10.1 (4.3) h. Following higher doses (> 10 mg) they were 2065-29,030 (16,470) ng/mL, 2.3-9.3 (4.5) h, 10.7-53.5 (34.4) h, 2.3-22.3 (8.3) h. Fmor peaked in the same sample as Tmor. Range (median) of peak Fmor concentrations and time to last positive using a cutoff of 100 ng/mL for low and high doses were, respectively, 117-1160 (415) ng/mL, 1.2-10.1 (4.5) h and 150-2580 (1400) ng/mL, 2.3-29.1 (9.3) h. The range (median) of peak urine concentrations for 6-AM was 6.1-568 (124) ng/mL. In general, the first urine void had the peak 6-AM concentration and was the only specimen positive at a 10-ng/mL cutoff. As previously reported urine concentrations varied greatly between subjects and within subjects with time after dosing but were much more predictable when values were reported as amount of drug per unit of creatinine. The range (median) values for percent of heroin excreted into urine as Tmor was 12.8-88.5% (51.0).

Administration, Inhalation↗