An Infant with a Prolonged Sympathomimetic Toxidrome after Lisdexamfetamine Dimesylate Ingestion.

INTRODUCTION: Stimulant medications are approved to treat attention deficit hyperactivity disorder (ADHD) in children over the age of 6 years. Fatal ingestion of stimulants by children has been reported, although most ingestions do not result in severe toxicity. Lisdexamfetamine dimesylate, a once daily long-acting stimulant, is a prodrug requiring conversion to its active form, dextroamphetamine, in the bloodstream. Based on its unique pharmacokinetics, peak levels of d-amphetamine are delayed. We describe a case of accidental ingestion of lisdexamfetamine dimesylate in an infant. CASE REPORT: A previously healthy 10-month-old infant was admitted to the hospital with a 5-h history of tachycardia, hypertension, dyskinesia, and altered mental status of unknown etiology. Confirmatory urine testing, from a specimen collected approximately 16 h after the onset of symptoms, revealed an urine amphetamine concentration of 22,312 ng/mL (positive cutoff 200 ng/mL). The serum amphetamine concentration, from a specimen collected approximately 37 h after the onset of symptoms, was 68 ng/mL (positive cutoff 20 ng/mL). Urine and serum were both negative for methamphetamine, methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA, Ecstasy), and methylenedioxyethamphetamine (MDEA). During the hospitalization, it was discovered that the infant had access to lisdexamfetamine dimesylate prior to the onset of symptoms. CONCLUSION: Amphetamine ingestions in young children are uncommon but do occur. Clinicians should be aware of signs and symptoms of amphetamine toxicity and consider ingestion when a pediatric patient presents with symptoms of a sympathetic toxidrome even when ingestion is denied.

First chemical synthesis of antioxidative metabolites of sesamin.

The first chemical synthesis of two metabolites ((1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo[3,3,0]octane (SC-1) and (1R,2S,5R,6S)-2,6-bis(3,4-dihydroxyphenyl)-3,7-dioxabicyclo[3,3,0]octane (SC-2)) of sesamin was achieved by a simple two-step approach from sesamin. The approach consists of acetoxylation of the methylenedioxy moiety(ies) with lead(IV) tetraacetate and acid hydrolysis of the resulting hemiorthoester to SC-1 and SC-2.

Quantitative NMR analysis of a sesamin catechol metabolite in human urine.

Sesamin, the major sesame oil lignan, is recognized for its health-promoting effects, including the lowering of cholesterol and elevation of gamma-tocopherol in rats and humans. However, little is known about the absorption and metabolism of sesamin in humans. In this study, 6 healthy volunteers took a single dose of sesame oil (508 micromol sesamin) and their urine was collected for four 12-h periods. The urine samples were treated with beta-glucuronidase/sulphatase and extracted with chloroform. The major urinary sesamin metabolite in the chloroform extract was collected using HPLC diode array detector and characterized as (1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane using NMR and mass spectroscopy. A quantitative (1)H-NMR technique, based on the methylenedioxyphenyl protons signal (delta 5.91), was used for the quantification of the metabolite in the chloroform extracts of urine. The excretion of the sesamin catechol metabolite ranged from 22.2 to 38.6% (mean +/- SD, 29.3 +/- 5.6) of the ingested dose and happened mainly in the 1st 12 h after ingestion.

Metabolism of trabectedin (ET-743, Yondelis) in patients with advanced cancer.

PURPOSE: Trabectedin (ET-743, Yondelis) is a novel anti-cancer drug currently undergoing phase II-III evaluation, that has shown remarkable activity in pre-treated patients with soft tissue sarcoma. Despite extensive pharmacokinetic studies, the human disposition and metabolism of trabectedin remain largely unknown. We aimed to determine the metabolic profile of trabectedin and to identify its metabolites in humans. METHODS: We analysed urine and faeces (the major excretory route) from eight cancer patients after a 3 or 24 h intravenous administration of [14C]trabectedin. Using liquid chromatography with tandem quadrupole mass spectrometric detection (LC-MS/MS) and radiochromatography with off-line radioactivity detection by liquid scintillation counting (LC-LSC), we characterised the metabolic profile in 0-24 h urine and 0-120 h faeces. RESULTS: By radiochromatography, a large number of trabectedin metabolites were detected. Incubation with beta-glucuronidase indicated the presence of a glucuronide metabolite in urine. Trabectedin, ET-745, ET-759A, ETM-259, ETM-217 (all available as reference compounds) and a proposed new metabolite coined ET-731 were detected using LC-MS/MS. The inter-individual differences in radiochromatographic profiles were small and did not correlate with polymorphisms in drug-metabolising enzymes (CYP2C9, 2C19, 2D6, 2E1, 3A4, GST-M1, P1, T1 and UGT1A1 2B15) as determined by genotyping. CONCLUSIONS: Trabectedin is metabolically converted to a large number of compounds that are excreted in both urine and faeces. In urine and faeces we have confirmed the presence of trabectedin, ET-745, ET-759A, ETM-259, ETM-217 and ETM-204. In addition we have identified a putative new metabolite designated ET-731. Future studies should be aimed at further identification of possible metabolites and assessment of their activity.

Sesamin is one of the major precursors of mammalian lignans in sesame seed (Sesamum indicum) as observed in vitro and in rats.

Plant lignans occur in many foods, with flaxseed presently recognized as the richest source. Some plant lignans can be converted by intestinal microbiota to the mammalian lignans, enterodiol and enterolactone, which may have protective effects against hormone-related diseases such as breast cancer. This study determined whether plant lignans in sesame seed, particularly sesamin, could be metabolized to the mammalian lignans. The total plant lignan concentration in sesame seed (2180 micromol/100 g) was higher than that in flaxseed (820 micromol/100 g). In vitro fermentation with human fecal inoculum showed conversion of sesamin to the mammalian lignans, although at a lower rate (1.1%) compared with that of secoisolariciresinol diglucoside (57.2%). However, when fed to female Sprague-Dawley rats for 10 d, sesamin (15 mg/kg body weight) and a 10% sesame seed diet resulted in greater (P < 0.05) urinary mammalian lignan excretion (3.2 and 11.2 micromol/d, respectively), than the control (< 0.05 micromol/d). We conclude that sesame seed is a rich source of mammalian lignan precursors and sesamin is one of them. From intermediate metabolites of sesamin identified in rat urine by GC-MS, a tentative metabolic pathway of sesamin to mammalian lignans is suggested.

Trabectedin (Yondelis, formerly ET-743), a mass balance study in patients with advanced cancer.

Trabectedin (Yondelis, formerly ET-743) is an anti-cancer drug currently undergoing phase II development. Despite extensive pharmacokinetic studies, the human disposition and excretory pathways of trabectedin remain largely unknown. Our objective was to determine the mass balance of trabectedin in humans. To this aim, we intravenously administered [(14)C]trabectedin to 8 cancer patients, followed by collection of whole blood, urine and faeces samples. A 24-h infusion was administered to 2 patients, whereas the other 6 patients received a 3-h infusion. Levels of total radioactivity and unchanged trabectedin were determined and used for calculation of pharmacokinetic parameters. No schedule dependency of pharmacokinetic parameters was observed apart from C(max). Plasma and whole blood concentrations of [(14)C]trabectedin related radioactivity were comparable. Only 8% of the plasma exposure to [(14)C]trabectedin related compounds is accounted for by trabectedin, indicating the importance of metabolism in trabectedin elimination. Trabectedin displays a large volume of distribution (+/-1700 L), relative to total radioactivity (+/-220 L). [(14)C]trabectedin related radioactivity is mainly excreted in the faeces (mean: 55.5% of the dose). Urinary excretion accounts for 5.9% of the dose on average resulting in a mean overall recovery of 61.4% (3-h administration schedule). The excretion of unchanged trabectedin is very low both in faeces and in urine (< 1% of dose). In conclusion, trabectedin is extensively metabolised and principally excreted in the faeces.

New designer drug 1-(3,4-methylenedioxybenzyl) piperazine (MDBP): studies on its metabolism and toxicological detection in rat urine using gas chromatography/mass spectrometry.

Studies are described on the metabolism and toxicological analysis of the piperazine-derived designer drug 1-(3,4-methylenedioxybenzyl)piperazine (MDBP) in rat urine using gas chromatography/mass spectrometry (GC/MS). The identified metabolites indicated that MDBP was metabolized by demethylenation and subsequent methylation to N-(4-hydroxy-3-methoxybenzyl)piperazine followed by partial glucuronidation or sulfation. Additionally, degradation of the piperazine moiety to N-(3,4-methylenedioxybenzyl)ethylenediamine and 3,4-methylenedioxybenzylamine and N-dealkylation to piperazine were observed. The authors' systematic toxicological analysis (STA) procedure using full-scan GC/MS after acid hydrolysis, liquid/liquid extraction and microwave-assisted acetylation allowed the detection of MDBP and its above-mentioned metabolites in rat urine after single administration of a dose calculated from the doses commonly taken by drug users. Assuming similar metabolism, the described STA procedure should be suitable for proof of an intake of MDBP by analysis of human urine.

Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man.

Ecteinascidin 743 (ET-743) is a potent anti-tumoral agent of a marine origin. It is currently being tested in phase II clinical trials using a 3-weekly 24-h i.v. infusion of 1500 microg/m(2) and 3-h infusions of 1650 microg/m(2). Knowledge of the metabolism of ET-743 is, however, still scarce. In the present study, a qualitative chromatographic discovery of metabolites of ET-743 in man is reported. ET-743 and its demethylated analog ET-729 were incubated at 37 degrees C in the presence of enzyme systems, pooled human microsomes, pooled human plasma and uridine 5'-diphosphoglucuronyltransferase, respectively, in appropriate media. Reaction products were investigated chromatographically using photodiode array and ion spray-mass spectrometric detection (LC-MS). The main reaction products in microsomal incubations of ET-743 resulted from a remarkable breakdown of the molecule. In plasma the drugs were deacetylated, and the transferase did actually yield a glucuronide of both ET-743 and ET-729. In contrast, screening of urine, plasma and bile, collected from patients treated with ET-743 at the highest dose levels, using a sensitive LC-MS assay, did not result in detection of ET-729 and metabolites which were generated in vitro. The urinary excretion of ET-743 in man was lower than 0.7% of the administered dose for a 24-h infusion.

[Use of 2H-labeled compound and GC-MS in the isolation and identification of a metabolite of biphenyldimethyl-dicarboxylate in rat urine].

Dimethyl-4, 4'-dimethoxy-5, 6, 5', 6'-dimethylenedioxy-biphenyl-2, 2'-dicarboxylate (biphenyldimethyldicarboxylate; BDD), a synthetic compound, has been used in the treatment of chronic hepatitis with good results in reducing s-GPT. Previous work in our laboratory studied its metabolites using 3H-labeled compound in combination with TLC and found that its main metabolic pathway is demethylation followed by conjugation with glucuronic acid. This paper reports the isolation and identification of a metabolite of BDD from rat urine using 2H-labeled compound and GC-MS. Rats fasted for 12 h were intragastrically given a mixture of 2H-labeled (consisting of monodeutero- and dideutero-BDD in the ratio about 1:1.3) and non-labeled BDD 150 mg/kg and placed in metabolism cages for urine collection. The 24 h urine was filtered and extracted three times each with 5 ml of methylenedichloride. The extracts were pooled and evaporated to dryness under reduced pressure at 35 degrees C. The residue was redissolved in chloroform and subjected to GC-MS analysis. The mass spectrum (m/z: 404, 405, 406; 373, 374, 375; 345, 346, 347; 330, 331, 332; etc) indicates that the molecular ionic and fragment peaks of the metabolite all have 14 amu less than those of BDD. This means that the metabolite isolated is mono-O-demethylated BDD. The result confirmed our findings reported previously.

Metabolism in rats of several carboxylic acid derivatives containing the 3,4-methylenedioxyphenyl group.

The metabolism of the 3,4-methylenedioxy derivatives of mandelic acid (1), phenylacetic acid (2), benzoic acid (3), 3-phenylpropionic acid (4) and cinnamic acid (5) was studied in rats. Following intragastric dosage (1 mmol/kg) the compounds and their metabolites were excreted in the urine within 24 hrs. Recoveries of roughly 85% were obtained. Except for compound (1) which was excreted to a large extent unchanged, glycine conjugates were the major urinary metabolites. Compound (2) formed 3,4-methylenedioxyphenylacetylglycine whereas compounds (3), (4) and (5) were converted to 3,4-methylenedioxybenzoylglycine. No evidence was found with any of the compounds for demethylenation and subsequent excretion of catecholic metabolites.