Amphetamine, clobenzorex, and 4-hydroxyclobenzorex levels following multidose administration of clobenzorex

Clobenzorex (Asenlix) is an anorectic drug used as part of a weight-management program. The drug is metabolized by the body to amphetamine, which is then excreted in the urine, thus causing difficulty in interpretation of amphetamine-positive drug tests. Previous studies have shown that the parent drug and several metabolites are excreted in urine. Clobenzorex itself has been detected for as long as 29 h following administration of a single dose. However, the parent drug was not always detected in samples that contained amphetamine at > or =500 ng/mL, the administrative cutoff for a positive result. Consequently, the parent compound clobenzorex is not ideal for ascertaining whether the drug was the origin of the amphetamine. Several metabolites of clobenzorex have been shown to be detected for a longer period of time than the parent. One of these, a hydroxy metabolite, was shown to be detected for an extended period of time. In a study of urine samples provided following administration of a single 30-mg dose of this drug, 4-hydroxyclobenzorex could be detected for up to 91.5 h. More significantly, that study showed all samples that were positive for amphetamine also contained detectable amounts of 4-hydroxyclobenzorex. This metabolite proved to be easily detected and was typically found at higher levels than amphetamine in urine samples positive for amphetamine long after clobenzorex itself could no longer be detected. The present study analyzed samples from a controlled multidose administration (30 mg of clobenzorex daily for seven days) for the presence of 4-hydroxyclobenzorex. The analytical procedure used acid hydrolysis followed by liquid-liquid extraction and gas chromatographic-mass spectrometric analysis with monitoring of ions at m/z 125, 330, and 364 for 4-hydroxyclobenzorex and its 3-Cl regioisomer, which was used as an internal standard. Peak concentrations of 4-hydroxyclobenzorex ranged from 17,786 to 99,044 ng/mL. Most importantly, this study also found that all samples that contained amphetamine at > or =500 ng/mL also contained detectable amounts of this hydroxy metabolite (LOD 10 ng/mL), making it a valuable tool in differentiating use of clobenzorex from illicit amphetamine use.     

Metabolic production of amphetamine following multidose administration of clobenzorex.

The interpretation of urine drug-testing results can have important forensic and legal implications. In particular, drugs that are metabolized to amphetamine or methamphetamine or both pose significant concerns. In this study, clobenzorex, an anorectic drug that is metabolized to d-amphetamine, was administered to five subjects. Each subject took 30 mg daily for seven days, and individual urine samples were collected ad lib for 14 days beginning on the first day the drug was administered. Urine pH, specific gravity, and creatinine values were determined for each sample. Gas chromatography-mass spectrometry (GC-MS) was used to determine the excretion profile of amphetamine and clobenzorex using a standard procedure for amphetamines with additional monitoring of ions at m/z 118, 125, and 364 for the detection of clobenzorex. Peak concentrations of amphetamine were found at 82 to 168 h after the first dose and ranged from approximately 2900 to 4700 ng/mL amphetamine. The use of a regioisomer (3-Cl-benzylamphetamine) as internal standard allowed for accurate quantitation of the parent drug. Peak concentrations of clobenzorex were found at 50 to 120 h after the first dose and ranged from approximately 8 to 47 ng/mL clobenzorex. However, in many samples, clobenzorex was not detected at all. This analysis revealed that the metabolite, (amphetamine) is present in much higher concentrations than the parent compound, clobenzorex. Yet even at peak amphetamine concentrations, the parent was not always detected (limit of detection 1 ng/mL). Thus, in the interpretation of amphetamine-positive drug-testing results, the absence of clobenzorex in the urine sample does not exclude the possibility of its use.     

Metabolic profile of famprofazone following multidose administration

One of the 14 different drugs known to be metabolized to methamphetamine and/or amphetamine is famprofazone, a component in the multi-ingredient formulation Gewodin. Because of its conversion to methamphetamine and amphetamine, which can result in positive drug-testing results, the excretion pattern of these metabolites is critical for proper interpretation of drug-testing results. Multiple doses of famprofazone were administered to healthy volunteers with no previous history of methamphetamine, amphetamine, or famprofazone use. Following administration, urine samples were collected ad lib for nine days, and pH, specific gravity, and creatinine values were determined. To determine the methamphetamine and amphetamine excretion profile, samples were extracted, derivatized, and analyzed by gas chromatography-mass spectrometry (GC-MS). Peak concentrations of methamphetamine ranged from 5327 to 14,155 ng/mL and from 833 to 3555 ng/mL for amphetamine and were reached between 12:22 and 48:45 h post initial dose. There were 15-19 samples per subject that were positive under HHS testing guidelines, with the earliest at 03:37 h post initial dose and as late as 70:30 h post last dose. Methamphetamine and amphetamine were last detected (LOD > or = 5 ng/mL) up to 159 h and 153 h post last dose for methamphetamine and amphetamine, respectively. GC-MS was also used to determine the enantiomeric composition of methamphetamine and amphetamine. This analysis revealed both enantiomers were present in a predictable pattern.     

A contemporaneous finding of fenproporex in a polydrug suicide

Fenproporex is a sympathomimetic agent with a pharmacological profile similar to that of amphetamine. It is available in many countries throughout the world, but it is currently not available in the United States. Because of its stimulant effects, it has a great potential for abuse. To the best of our knowledge, there have been no literature reports of blood or serum concentrations found in therapeutic, toxic, or fatal cases. We report a case where fenproporex was a finding in the death of a young adult. Blood, urine, and gastric contents were analyzed. The following drug concentrations were found: 0.90 mg/L (inferior vena cava blood), 1.2 mg/L (urine), and 120 mg total (gastric) for fenproporex and 0.084 mg/L (inferior vena cava blood), 0.94 mg/L (urine), and 0.14 mg total (gastric) for amphetamine. In addition to the fenproporex, other medications detected and their blood concentrations found in this case were H diazepam (0.54 mg/L), nordiazepam (0.46 mg/L), diphenhydramine (0.12 mg/L), and gamma hydroxybutyric acid (GHB) (1100 mg/L).     

Differentiation of clobenzorex use from amphetamine abuse using the metabolite 4-hydroxyclobenzorex

Clobenzorex (Asenlix) is an anorectic drug metabolized by the body to amphetamine, thus causing difficulty in the interpretation of amphetamine-positive drug tests. Previous studies have shown the parent drug and several metabolites are excreted in urine. Clobenzorex itself has been detected for as long as 29 h postdose using a detection limit of 1 ng/mL. Despite this fact, several amphetamine-positive samples (> or = 500 ng/mL) contained no detectable clobenzorex. Thus, the absence of clobenzorex in the urine does not exclude the possibility of its use. To more definitively assess the possibility of clobenzorex use, evaluation of another metabolite was considered. One study reported the presence of unidentified hydroxy metabolites of clobenzorex for as long as amphetamine was detected in some subjects. To assess the viability of using a hydroxy metabolite to confirm the use of clobenzorex in samples containing amphetamine, 4-hydroxyclobenzorex was synthesized for this study. This metabolite proved to be easily detected and was typically found at levels higher than amphetamine in amphetamine-positive urines, long after clobenzorex itself was no longer detected. Samples obtained from a controlled single-dose study involving the administration of clobenzorex (30 mg) were analyzed for the presence of the 4-hydroxy metabolite. The analytical procedure used acid hydrolysis followed by liquid-liquid extraction and analysis with gas chromatography-mass spectrometry by monitoring ions at m/z 125, 330, and 364. 4-Hydroxyclobenzorex and its 3-Cl regioisomer were used in the identification and quantitation of the metabolite. Peak concentrations of 4-hydroxyclobenzorex were found at approximately 1:30-5:00 h postdose and ranged from approximately 5705 to 88,410 ng/mL. Most importantly, however, all samples that contained amphetamine at > or = 500 ng/mL also contained detectable amounts of this hydroxy metabolite (LOD 10 ng/mL), making it a valuable tool in differentiating use of clobenzorex from illicit amphetamine use.     

A gas chromatography-mass spectrometry method for the quantitation of clobenzorex

Drugs metabolized to amphetamine or methamphetamine are potentially significant concerns in the interpretation of amphetamine-positive urine drug-testing results. One of these compounds, clobenzorex, is an anorectic drug that is available in many countries. Clobenzorex (2-chlorobenzylamphetamine) is metabolized to amphetamine by the body and excreted in the urine. Following administration, the parent compound was detectable for a shorter time than the metabolite amphetamine, which could be detected for days. Because of the potential complication posed to the interpretation of amphetamin-positive drug tests following administration of this drug, the viability of a current amphetamine procedure using liquid-liquid extraction and conversion to the heptafluorobutyryl derivative followed by gas chromatography-mass spectrometry (GC-MS) analysis was evaluated for identification and quantitation of clobenzorex. Qualitative identification of the drug was relatively straightforward. Quantitative analysis proved to be a far more challenging process. Several compounds were evaluated for use as the internal standard in this method, including methamphetamine-d11, fenfluramine, benzphetamine, and diphenylamine. Results using these compounds proved to be less than satisfactory because of poor reproducibility of the quantitative values. Because of its similar chromatographic properties to the parent drug, the compound 3-chlorobenzylamphetamine (3-Cl-clobenzorex) was evaluated in this study as the internal standard for the quantitation of clobenzorex. Precision studies showed 3-Cl-clobenzorex to produce accurate and reliable quantitative results (within-run relative standard deviations [RSDs] < 6.1%, between-run RSDs < 6.0%). The limits of detection and quantitation for this assay were determined to be 1 ng/mL for clobenzorex.     

Amphetamine concentrations in human urine following single-dose administration of the calcium antagonist prenylamine-studies using fluorescence polarization immunoassay (FPIA) and GC-MS

Prenylamine (R,S-N-(3,3-diphenylpropyl-methyl-2-phenethylamine), a World Health Organization class V calcium antagonist, is known to be metabolized to amphetamine. In this study, amphetamine concentrations after a single-dose administration of prenylamine were determined to check if they reached values that could be of analytical and/or pharmacological importance in clinical and forensic toxicology. Enantiomeric composition of amphetamine was also studied. Five volunteers received a single 120-mg oral dose of prenylamine. Urine samples were analyzed using the Abbott TDx immunoassay Amphetamine/Methamphetamine II and using our routine systematic toxicological analysis (STA) gas chromatography-mass spectrometry (GC-MS) procedure. For quantitation purposes, GC-MS was used in the selected-ion monitoring (SIM) mode (ions m/z 118, 122, 240, 244) after solid-phase extraction (Isolute Confirm HCX) and derivatization (heptafluorobutyric anhydride). Amphetamine-d5 was used as internal standard (IS). Chiral separation of the heptafluorobutyrated amphetamine enantiomers was achieved using an Astec Chiraldex G-PN column. The TDx results showed a great variability for the different volunteers. A urine sample of one volunteer showed results as high as 3200 ng/mL, whereas the urine samples of another volunteer never gave results greater than the TDx detection limit (100 ng/mL). Using the STA procedure, the presence of amphetamine could be confirmed in all urine samples with TDx results greater than the cutoff value (300 ng/mL). Using the GC-MS SIM method, amphetamine concentrations up to 1280 ng/mL were determined. Chiral analysis revealed that both enantiomers of amphetamine were present in the samples with a surplus of the S(+)-enantiomer in the early phase of excretion. Forensic implications are discussed.     

Developmental exposure to fenproporex: reproductive and morphological evaluation

This study was designed to evaluate the maternal toxicity and teratogenicity of fenproporex, one of the most widely-used anorectic drugs in many countries, including Brazil. Three periods of exposure were evaluated: (a) 30 days before mating; (b) from gestational day (GD) 0 to 14; and (c) 30 days before mating and during pregnancy, until GD 14. Female mice from experimental groups received, by gavage, 15 mg/kg of fenproporex. Treatment with fenproporex increased ambulation of dams in the open-field test and did not influence the mobility in the forced-swimming test. There was no significant difference in maternal weight gain between the controls and fenproporex-treated groups, although fenproporex treatment reduced the gravid uterus weight. No significant difference was observed in postimplantation loss, fetal viability and sex ratio. In addition, this compound did not impair intra-uterine growth. The reduction in the number of implantations in the groups receiving fenproporex indicates that this drug may have an adverse effect on implantation. Fenproporex treatment also increased the number of fetuses presenting small kidneys and cervical ribs. The present results indicate that fenproporex, in the dose and exposure periods tested, appears to exhibit a low maternal toxicity and teratogenic potential in mice.     

Pharmacokinetics of dextromethorphan and its metabolites in horses following a single oral administration

Dextromethorphan is an N‐methyl‐D‐aspartate (NMDA) non‐competitive antagonist commonly used in human medicine as an antitussive. Dextromethorphan is metabolized in humans by cytochrome P450 2D6 into dextrorphan, which is reported to be more potent than the parent compound. The goal of this study is to describe the metabolism of and determine the pharmacokinetics of dextromethorphan and its major metabolites following oral administration to horses. A total of 23 horses received a single oral dose of 2 mg/kg. Blood samples were collected at time 0 and at various times up to 96 h post drug administration. Urine samples were collected from 12 horses up to 120 h post administration. Plasma and urine samples were analyzed using liquid chromatography‐mass spectrometry, and the resulting data analyzed using non‐compartmental analysis. The C_max, T_max, and the t_1/2 of dextromethorphan were 519.4 ng/mL, 0.55 h, and 12.4 h respectively. The area under the curve of dextromethorphan, free dextrorphan, and conjugated dextrorphan were 563.8, 2.19, and 6,691 h*ng/mL respectively. In addition to free and glucuronidated dextrorphan, several additional glucuronide metabolites were identified in plasma, including hydroxyl‐desmethyl dextrorphan, desmethyl dextrorphan, and three forms of hydroxylated dextrorphan. Dextromethorphan was found to be eliminated from the urine predominately as the O‐demethylated metabolite, dextrorphan. Several additional metabolites including several novel hydroxy‐dextrorphan metabolites were also detected in the urine in both free and glucuronidated forms. No significant undesirable behavioural effects were noted throughout the duration of the study. Copyright © 2016 John Wiley & Sons, Ltd.     

Characterization of the solubility of a poorly soluble hydroxylated metabolite in human urine and its implications for potential renal toxicity

The solubility, in human urine, of the major hydroxylated metabolite (M1) of an experimental cognition enhancer was characterized through a series of in vitro experiments in an effort to estimate the probability of crystalluria occurring following oral administration of the parent compound. The aim of these experiments was to determine if a safety margin existed between clinically observed urine concentrations and the solubility of M1. The mean urine concentrations of M1 in young and elderly subjects following oral administration of the parent compound at the highest doses tested, were 4865 +/- 2368 ng/mL and 2764 +/- 791 ng/mL, respectively. In vitro solubility experiments with M1 were conducted in drug-free human urine (37 degrees C) from four male and four female healthy subjects under conditions of high and low urine osmolality. Mean concentrations (n = 16) of M1 in human urine to which solid M1 was added, were 3656 +/- 621 ng/mL, 4678 +/- 1169 ng/mL and 5378 +/- 2474 ng/mL after stirring for 24, 48 and 72 h, respectively, indicating that the ex vivo mean solubility of M1 in human urine is no greater then approximately 5 microg/mL. Addition of solid M1 to urine from human subjects dosed with the parent compound resulted in mean urine M1 concentrations 23.5% greater than those observed in vivo. The results from both experiments indicated a significant overlap between urine concentrations of M1 in vivo following the highest oral administration of the parent drug and M1 solubility measured in vitro, suggesting a high potential for in vivo saturation of urine with M1 with subsequent precipitation, crystalluria, and nephrotoxicity. Consequently, the results of these studies have placed restrictions on the dose that could be administered during clinical development of this compound.     

Detection of ketamine and norketamine in urine of nonhuman primates after a single dose of ketamine using microplate enzyme-linked immunosorbent assay (ELISA) and NCI-GC-MS

The general anesthetic ketamine (Ketalar, Ketaject, Vetalar) (KET) is used in human and veterinary medicine for induction of anesthesia for short surgical procedures and routine veterinary examination. Its illicit use by teenagers in rave parties has been reported, and it has recently been identified as a substance associated with sexual assault. One aim of this paper was to study the elimination of KET and its major metabolite norketamine (NKET) in urine collected from five nonhuman primates that received a single dose (5 mg/kg, I.M.) of KET and to study elimination patterns to determine how long after drug administration KET and NKET can be detected. Another aim of this study was to develop and validate a highly sensitive negative ion chemical ionization-gas chromatography-mass spectrometry (NCI-GC-MS) method for the simultaneous quantitation of KET and its major metabolite NKET in urine and to analyze urine samples collected from the animals. The last aim of this study was to apply and evaluate a newly developed ELISA screening methodology for detection of KET and its metabolites in the same urine samples collected from primates which received a single dose of KET. In two monkeys, KET was detected in urine up to 3 days after drug administration (32-7070 ng/mL); in one monkey, it was detected up to 4 days (65-13,500 ng/mL); in one monkey, it was detected only on days 1 and 2 (4000 and 70 ng/mL, respectively); and in one monkey, it was detected 10 days after KET injection (22-35,000 ng/mL). NKET concentrations ranged from 63 pg/mL to 1.75 microg/mL, and it remained in the urine throughout the entire 35-day study period in 4 out of 5 animals. In one monkey, NKET was detected up to 31 days after KET administration. Urine analysis using ELISA revealed that KET and NKET can be easily detectable at 25 ng/mL. In one monkey, KET and its metabolites were detected in urine up to 4 days after drug administration, up to 7 days in two monkeys, up to 11 days in one monkey, and 16 days after KET injection in one monkey. Urine extraction followed by screening using ELISA methodology allowed for significant extension of the detection period in all animals from the study. It is believed that the KET elimination in urine of nonhuman primates is slightly faster than in humans. We propose that NCI-GC-MS be employed to detect NKET as a target compound in urine in toxicological investigations of drug-facilitated sexual assault when KET use by the perpetrator is suspected.     

Comparison of saliva and urine samples in thin-layer chromatographic detection of central nervous stimulants

The excretion of amphepramone, amphetamine, ephedrine and prolintane was estimated qualitatively from saliva and urine using thin-layer chromatography (TLC) 1, 2, 4, 8, 12 and 24 h after a single intake of therapeutic doses by healthy volunteers. The purpose was to compare the suitability of these two biological fluids for doping tests and it was therefore important that either the drug or its metabolites should be found in all subjects. Ephedrine was the only one to be detected regularly in saliva already 1 h after drug intake, and it was found there up to 8 h, while in urine it was found up to 24 h. In saliva, prolintane or its main metabolite did not appear during 24 h, whereas it or its metabolite were consistently found in urine 4-12 h after drug intake. Neither amphepramone nor its metabolites were detected at any time in saliva, but this drug was found, either in unchanged or in metabolized form, in urine 1-24 h after intake. The same was true for amphetamine, except at 1 h in urine. The findings did not clearly correlate with the pH of either saliva or urine samples. It is concluded that in TLC screening saliva is inferior to urine in doping tests.     

Morphine and etorphine: XIV. Detection by ELISA in equine urine.

We have raised antibodies to morphine and etorphine and developed one-step enzyme-linked immunosorbent assays (ELISA) for these drugs as part of a panel of post race tests for drugs in racing horses. These tests are simple, can be completed in 2 h, and can be read by visual inspection. The morphine ELISA has an I50 for morphine of about 1.5 ng/mL, while the etorphine ELISA has an I50 for etorphine of 250 pg/mL. Cross-reactivity studies show that the antimorphine antibody cross-reacts well with levorphanol, hydromorphone, and oxycodone, while the anti-etorphine antibody showed no cross-reactivity with buprenorphine, diprenorphine, oxymorphone, morphine, or thebaine. The morphine test readily detected parent morphine or its metabolites in equine urine for at least 8 h after administration of 50 mg/horse, while a 0.1 micrograms/kg dose of etorphine was detectable for up to 48 h post dosing. For each test the background activity in post-race urines was equal to or less than the I50 for the standard curves, making them useful equine forensic tests. Each of these tests has detected "positives" in post race urine samples and as such these tests are capable of substantially improving the speed and efficacy of both pre-race and post-race testing for morphine, etorphine, and their congeners in racing horses.     

Detection of opiate use in a methadone maintenance treatment population with the CEDIA 6-acetylmorphine and CEDIA DAU opiate assays

Heroin, with a plasma half-life of approximately 5 min, is rapidly metabolized to 6-acetylmorphine (6-AM). 6-AM, a specific marker for heroin use, which also has a short half-life of only 0.6 h, is detected in urine for only a few hours after heroin exposure. Ingestion of poppy seeds and/or licit opiate analgesics can produce positive urine opiate tests. This has complicated the interpretation of positive opiate results and contributed to the decision to raise opiate cutoff concentrations and to require 6-AM confirmation in federally mandated workplace drug-testing programs. Microgenics Corp. has developed the CEDIA 6-AM assay, a homogeneous enzyme immunoassay for semiquantitative determination of 6-AM in human urine, in addition to its CEDIA DAU opiate assay. Urine specimens were collected 3 times per week from 27 participants enrolled in a clinical research trial evaluating a contingency management treatment program for heroin and cocaine abuse. Of the 1377 urine specimens screened, 261 (18.9%) were positive for opiates at > or = 300 ng/mL, 153 (11.1%) were positive for opiates at > or = 2000 ng/mL, and 55 (4.0%) were positive for 6-AM at > or = 10 ng/mL. For opiate-positive screens > or = 300 and > or = 2000 ng/mL, 91.3% and 80.8% confirmed positive for morphine or codeine at the respective gas chromatography-mass spectrometry (GC-MS) cutoffs. All specimens screening positive for 6-AM also confirmed positive by GC-MS at > or = 10 ng/mL. Increasing the opiate screening and confirmation cutoffs for the federal workplace drug-testing program resulted in 8% fewer opiate-positive tests; however, recent heroin use was not affected by this change.     

Major and minor metabolites of cocaine in human plasma following controlled subcutaneous cocaine administration

Cocaine is rapidly metabolized to major metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME), and minor metabolites, norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine. This IRB-approved study examined cocaine and metabolite plasma concentrations in 18 healthy humans who provided written informed consent to receive low (75 mg/70 kg) and high (150 mg/70 kg) subcutaneous cocaine hydrochloride doses. Plasma specimens, collected prior to and up to 48 h after dosing, were analyzed by gas chromatography-mass spectrometry (2.5 ng/mL limits of quantification). Cocaine was detected within 5 min, with mean+/-SE peak concentrations of 300.4+/-24.6 ng/mL (low) and 639.1+/-56.8 ng/mL (high) 30-40 min after dosing. BE and EME generally were first detected in plasma 5-15 min post-dose; 2-4 h after dosing, BE and EME reached mean maximum concentrations of 321.3+/-18.4 (low) and 614.7+/-46.0 ng/mL (high) and 47.4+/-3.0 (low) and 124.4+/-18.2 ng/mL (high), respectively. Times of last detection were BE>EME>cocaine. Minor metabolites were detected much less frequently for up to 32 h, with peak concentrations相似文献   

Methamphetamine in antemortem blood and urine by radioimmunoassay and GC/MS

Methamphetamine abuse is increasing and methamphetamine is second only to alcohol as a positive finding in cases submitted to the San Diego Sheriff's Crime Laboratory. In general, whole blood specimens are submitted more often than urine. A modified version of a commercially available radioimmunoassay, Coat-A-Count (CAC) Methamphetamine, was investigated as a screen for methamphetamine in whole blood and urine. The assay was modified by using 100 microL of sample, making up standards in whole beef blood, extending the incubation time to 2 h or overnight, and using a cutoff reference of 50 ng/mL methamphetamine. The detection limit for the CAC Methamphetamine kit was 20 ng/mL methamphetamine in whole blood. The CAC Methamphetamine results were compared to Abuscreen Amphetamine High Specificity results and to gas chromatography/mass spectrometry (GC/MS) quantitation of amphetamine and methamphetamine for 157 positive and 48 negative blood specimens. With the CAC Methamphetamine assay there were 2 false negatives detected, both less than the 50 ng/mL cutoff level. There were 12 (6%) false positives with the CAC Methamphetamine assay and 29 (14%) false positives with the Abuscreen Amphetamine assay. Of the positive samples, 95% contained only methamphetamine, with an average concentration of 308 ng/mL, range 25-2030 ng/mL.     

Urinary pharmacokinetics of methamphetamine and its metabolite, amphetamine following controlled oral administration to humans

Methamphetamine is widely abused for its euphoric effects. Our objectives were to characterize the urinary pharmacokinetics of methamphetamine and amphetamine after controlled methamphetamine administration to humans and to improve the interpretation of urine drug test results. Participants (n = 8) received 4 daily 10-mg (low) oral doses of sustained-release (d)-methamphetamine hydrochloride within 7 days. After 4 weeks, 5 participants received 4 daily 20-mg (high) oral doses. All urine specimens were collected during the study. Methamphetamine and amphetamine were measured by GC-MS/PCI. Maximum excretion rates ranged from 403 to 4919 microg/h for methamphetamine and 59 to 735 microg/h for amphetamine with no relationship between dose and excretion rate. The mean molar percentage of dose in the urine as total methamphetamine and amphetamine were 57.5 +/- 21.7% (low dose) and 40.9 +/- 8.5% (high dose). Mean urinary terminal elimination half-lives across doses were 23.6 +/- 6.6 hours for methamphetamine and 20.7 +/- 7.3 hours for amphetamine. Methamphetamine renal clearance across doses was 175 +/- 102 mL/min. The mean amphetamine/methamphetamine percentage ratio based on the area under the urinary excretion-time curve increased over time from 13.4 +/- 6.5% to 35.7 +/- 26.6%. Slow urinary excretion results in drug accumulation and increases in detection time windows. Our findings also support the presence of an active renal excretion mechanism for methamphetamine.