Direct Analysis of Conjugate Metabolites of Methamphetamine, 3,4-Methylenedioxymethamphetamine, and Their Designer Drugs in Biological Fluids

Shima, Noriaki; Katagi, Munehiro; Tsuchihashi, Hitoshi

doi:10.1248/jhs.55.495

Cited by 11 publications

(7 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here we showed methamphetamine and its metabolites interact with hOCT1-3 and hMATE1/2-K at clinically relevant concentrations (Melega et al, 2007;Shima et al, 2009). We further demonstrated that methamphetamine and amphetamine are substrates of hOCT2, hMATE1, and hMATE2-K, but not hOCT1or hOCT3.…”

Section: Discussionsupporting

confidence: 57%

Interaction and Transport of Methamphetamine and its Primary Metabolites by Organic Cation and Multidrug and Toxin Extrusion Transporters

et al. 2017

View full text Add to dashboard Cite

Methamphetamine is one of the most abused illicit drugs with roughly 1.2 million users in the United States alone. A large portion of methamphetamine and its metabolites is eliminated by the kidney with renal clearance larger than glomerular filtration clearance. Yet the mechanism of active renal secretion is poorly understood. The goals of this study were to characterize the interaction of methamphetamine and its major metabolites with organic cation transporters (OCTs) and multidrug and toxin extrusion (MATE) transporters and to identify the major transporters involved in the disposition of methamphetamine and its major metabolites, amphetamine and -hydroxymethamphetamine (-OHMA). We used cell lines stably expressing relevant transporters to show that methamphetamine and its metabolites inhibit human OCTs 1-3 (hOCT1-3) and hMATE1/2-K with the greatest potencies against hOCT1 and hOCT2. Methamphetamine and amphetamine are substrates of hOCT2, hMATE1, and hMATE2-K, but not hOCT1 and hOCT3. -OHMA is transported by hOCT1-3 and hMATE1, but not hMATE2-K. In contrast, organic anion transporters 1 and 3 do not interact with or transport these compounds. Methamphetamine and its metabolites exhibited complex interactions with hOCT1 and hOCT2, suggesting the existence of multiple binding sites. Our studies suggest the involvement of the renal OCT2/MATE pathway in tubular secretion of methamphetamine and its major metabolites and the potential of drug-drug interactions with substrates or inhibitors of the OCTs. This information may be considered when prescribing medications to suspected or known abusers of methamphetamine to mitigate the risk of increased toxicity or reduced therapeutic efficacy.

show abstract

Section: Discussionsupporting

confidence: 57%

Interaction and Transport of Methamphetamine and its Primary Metabolites by Organic Cation and Multidrug and Toxin Extrusion Transporters

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Many reviews have focused on the drugs of abuse themselves, [5][6][7][8] specific biological specimens, such as hair, 9,10) the methodology, 11,12) or the analytical instruments. [2][3][4] In this review, on the basis of reports published in the last three years (2008-2010) describing the analyses of drugs of abuse in biological specimens, different perspectives, such as the need for and the background of drug analysis in biological specimens, and difficulty of drug testing in biological specimens, are introduced together with some actual examples.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Drugs of Abuse in Biological Specimens

Saito

Kikuchi

et al. 2011

JOURNAL OF HEALTH SCIENCE

View full text Add to dashboard Cite

Recent reports of the analysis of drugs of abuse in biological specimens are reviewed herein. Different perspectives from reviews so far published and the need for and the background of drug analysis in biological specimens, and difficulty of drug testing in biological specimens are introduced. Comprehensive biological specimens for the analysis of drugs of abuse in forensic science, including oral fluid (saliva), hair, umbilical cord, placenta, meconium, cadaver tissue (brain, adipose), sweat, breath, and nail clippings, in addition to the commonly used blood and urine specimens in clinical chemistry, are described along with their outlines, advantages/disadvantages, and actual examples. Today, liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the method of choice for the analysis of drugs of abuse. A simultaneous screening method for multiple types of drugs has also become popular recently. However, because qualitative determination remains important in forensic science, gas chromatographymass spectrometry (GC-MS) is still in use even if it requires complicated specimen preparation and derivatization procedures. This is because GC-MS is reliable and has been employed ever since for the appraisal of trials.

show abstract

“…27 In accordance, Phase II glucuronide products of methamphetamine metabolism were targeted by the comprehensive methamphetamine metabolism analysis method employed in the present study. In contrast to human specimen data reported in previous work, direct LC-MS analysis in the present study was unable to detect methamphetamine metabolite glucuronide formation in any in vitro system examined, despite the presence of active Phase I oxidation and Phase II glucuronidation mechanisms.…”

Section: Methamphetamine Metabolism Discussionmentioning

confidence: 99%

“…27 While minor differences in quantities of hydroxylated metabolites were noted between assays containing the cofactors necessary to form glucuronide conjugates (+1/2) and those lacking UDP-GlcUA (+1), the analysis method did not directly detect the presence of glucuronic acid conjugated metabolites. …”

Section: Secondary Metabolitesmentioning

confidence: 93%

“…26 The numerous hydroxylated products produced allow for subsequent conjugation of methamphetamine metabolic products via Phase II conjugation to glucuronide or sulfate moieties. 27 As a result of the chemical nature of sympathomimetic amines, the metabolism of methamphetamine produces numerous pharmacologically active metabolites such as amphetamine.…”

Section: Cytochrome P450 Isozymesmentioning

confidence: 99%

See 1 more Smart Citation

Covalent Protein Adduction by Drugs of Abuse

Schneider¹

View full text Add to dashboard Cite

Recreational abuse of the drugs cocaine, methamphetamine, and morphine continues to be prevalent in the United States of America and around the world. While numerous methods of detection exist for each drug, they are generally limited by the lifetime of the parent drug and its metabolites in the body. However, the covalent modification of endogenous proteins by these drugs of abuse may act as biomarkers of exposure and allow for extension of detection windows for these drugs beyond the lifetime of parent molecules or metabolites in the free fraction. Additionally, existence of covalently bound molecules arising from drug ingestion can offer insight into downstream toxicities associated with each of these drugs.This research investigated the metabolism of cocaine, methamphetamine, and morphine in common in vitro assay systems, specifically focusing on the generation of reactive intermediates and metabolites that have the potential to form covalent protein adducts. Results demonstrated the formation of covalent adduction products between biological cysteine thiols and reactive moieties on cocaine and morphine metabolites. Rigorous mass spectrometric analysis in conjunction with in vitro metabolic activation, pharmacogenetic reaction phenotyping, and computational modeling were utilized to characterize structures and mechanisms of formation for each resultant thiol adduction product. For cocaine, data collected demonstrated the formation of adduction products from a reactive arene epoxide intermediate, designating a novel metabolic pathway for cocaine. In the case of morphine, data expanded on known adduct-forming pathways using sensitive and selective analysis techniques, following the known reactive metabolite, morphinone, and a proposed novel metabolite, morphine quinone methide. Data collected in this study describe novel metabolic events for multiple important drugs of abuse, culminating v in detection methods and mechanistic descriptors useful to both medical and forensic investigators when examining the toxicology associated with cocaine, methamphetamine, and morphine.

show abstract

Direct Analysis of Conjugate Metabolites of Methamphetamine, 3,4-Methylenedioxymethamphetamine, and Their Designer Drugs in Biological Fluids

Cited by 11 publications

References 34 publications

Interaction and Transport of Methamphetamine and its Primary Metabolites by Organic Cation and Multidrug and Toxin Extrusion Transporters

Interaction and Transport of Methamphetamine and its Primary Metabolites by Organic Cation and Multidrug and Toxin Extrusion Transporters

Analysis of Drugs of Abuse in Biological Specimens

Covalent Protein Adduction by Drugs of Abuse

Contact Info

Product

Resources

About