Metabolism of the new designer drug α-pyrrolidinopropiophenone (PPP) and the toxicological detection of PPP and 4′-methyl-α-pyrrolidinopropiophenone (MPPP) studied in rat urine using gas chromatography-mass spectrometry

Springer, Dietmar; Fritschi, Giselher; Maurer, Hans H.

doi:10.1016/j.jchromb.2003.07.008

Cited by 80 publications

(80 citation statements)

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“…Characterizing NPS metabolic pathways is imperative for PK profiling and understanding PD effects. The metabolic pathways of other α-pyrrolidinophenones, including MDPV, α-PVP, α-PBP, α-PPP, 4-methyl-α-pyrrolidonophene, 4-methoxy-α-pyrrolidinophenone and 4-methyl-α-pyrrolidinohexiophenone were previously investigated in human liver microsomes (HLM) and rat urine [17][18][19][20][21][22][23][24][25][26][27]. In a recent review of pyrrolidinophenones' pharmacology, Zaitsu et al summarized the main metabolites to include ketone reduction to the corresponding alcohol and oxidation to the 2'-oxo metabolites [28].…”

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In Vitro, in Vivo and In Silico Metabolic Profiling of α-Pyrrolidinopentiothiophenone, A Novel Thiophene Stimulant

et al. 2015

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Background: Little or no pharmacological or toxicological data are available for novel psychoactive substances when they first emerge, making their identification and interpretation in biological matrices challenging. Materials & methods: A new synthetic cathinone, α-pyrrolidinopentiothiophenone (α-PVT), was incubated with hepatocytes and samples were analyzed using liquid chromatography coupled to a Q Exactive TM Orbitrap mass spectrometer. Authentic urine specimens from suspected α-PVT cases were also analyzed. Scans were data mined with Compound Discoverer™ for identification and structural elucidation of metabolites. Results/conclusion: Seven α-PVT metabolites were identified in hepatocyte incubations, and in the authentic urine samples, also with an additional monohydroxylated product and a glucuronide of low intensity. α-PVT dihydroxypyrrolidinyl, α-PVT 2-ketopyrrolidinyl, α-PVT hydroxythiophenyl and α-PVT thiophenol had the most intense in vivo signals.

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In Vitro, in Vivo and In Silico Metabolic Profiling of α-Pyrrolidinopentiothiophenone, A Novel Thiophene Stimulant

et al. 2015

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“…MPPP has been scheduled in the German Act of Controlled Substances after large amounts of tablets were distributed for recreational use and seized by the police (Roesner et al, 1999). Routine drugs of abuse screenings do not allow the detection of MPPP in biosamples (Springer et al, 2002). Although little information about its pharmacological and toxicological properties is available, amphetamine-like effects can be predicted, since structurally similar anorectics like amfepramone and metamfepramone, drugs of abuse like cathinone and methcathinone, and antidepressants like bupropion are based on this mode of action (Bryant et al, 1983;Kalix and Glennon, 1986;Glennon et al, 1987;Martinez et al, 1998).…”

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“…1) followed by dehydrogenation to the corresponding carboxylic acid (Springer et al, 2002). The aim of the study reported here was to identify the human hepatic cytochrome P450 (P450) enzymes involved in the hydroxylation and to determine the kinetic constants for this metabolic reaction.…”

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IDENTIFICATION OF CYTOCHROME P450 ENZYMES INVOLVED IN THE METABOLISM OF 4′-Methyl-Α-Pyrrolidinopropiophenone, a NOVEL SCHEDULED DESIGNER DRUG, IN HUMAN LIVER MICROSOMES

Springer¹,

Paul²,

Staack³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:4 -Methyl-␣-pyrrolidinopropiophenone (MPPP) is a new drug of abuse. It is believed to have an abuse potential similar to that of amphetamines. Previous studies with Wistar rats had shown that MPPP was metabolized mainly by hydroxylation in position 4 followed by dehydrogenation to the corresponding carboxylic acid. The aim of the study presented here was to identify the human hepatic cytochrome P450 (P450) enzymes involved in the biotransformation of MPPP to 4 -hydroxymethyl-pyrrolidinopropiophenone. Baculovirus-infected insect cell microsomes and human liver microsomes were used for this purpose. Only CYP2C19 and CYP2D6 catalyzed this hydroxylation. The apparent K m and V max values for the latter were 9.8 ؎ 2.5 M and 13.6 ؎ 0.7 pmol/min/pmol P450, respectively. 4Ј-Methyl-␣-pyrrolidinopropiophenone [MPPP 1 , international nonproprietary name: 2-(pyrrolidine-1-yl)-1-( p-tolyl)propane-1-one] is a new designer drug that has appeared on the illicit drug market. MPPP has been scheduled in the German Act of Controlled Substances after large amounts of tablets were distributed for recreational use and seized by the police (Roesner et al., 1999). Routine drugs of abuse screenings do not allow the detection of MPPP in biosamples (Springer et al., 2002). Although little information about its pharmacological and toxicological properties is available, amphetamine-like effects can be predicted, since structurally similar anorectics like amfepramone and metamfepramone, drugs of abuse like cathinone and methcathinone, and antidepressants like bupropion are based on this mode of action (Bryant et al., 1983;Kalix and Glennon, 1986;Glennon et al., 1987;Martinez et al., 1998). Possible clinical effects of MPPP include tachycardia, hypertension, mydriasis, and tremor.Previous in vivo studies in rats showed that MPPP was mainly metabolized by hydroxylation of the 4Ј-methyl group (Fig. 1) followed by dehydrogenation to the corresponding carboxylic acid (Springer et al., 2002). The aim of the study reported here was to identify the human hepatic cytochrome P450 (P450) enzymes involved in the hydroxylation and to determine the kinetic constants for this metabolic reaction. Materials and MethodsMaterials. MPPP-HCl and MDPPP-HCl (3Ј,4Ј-methylenedioxy-␣-pyrrolidinopropiophenone, international nonproprietary name: 1-(1,3-benzodioxol-5-yl)-2-(pyrrolidine-1-yl)propane-1-one) were provided by the Hessian State Criminal Office (Wiesbaden, Germany), before the compounds had entered the German Act of Controlled Substances. NADP ϩ was obtained from Biomol (Hamburg, Germany), isocitrate, and isocitrate dehydrogenase from Sigma (Taufkirchen, Germany), all other chemicals and reagents from Merck (Darmstadt, Germany). The following microsomes were purchased from NatuTec (Frankfurt/Main, Germany): baculovirus-infected insect cell microsomes containing 1 nmol/ml CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 (Supersomes), wild-type baculovirus-infecte...

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“…A partir de uma única dose desta substância, pode ser observado aumento do tônus muscular, dificuldade de movimentos e fala, salivação e rigidez das extremidades superiores. 23,25,26 Alguns derivados opioides são encontrados no material biológico em concentrações muito baixas, e nestas concentrações não podem ser detectados por meio de triagem com procedimentos rotineiramente empregados. Portanto, métodos diretos de determinação deste grupo de compostos são necessários.…”

Section: Derivados Opioidesunclassified

Designer drugs: aspectos analíticos e biológicos

Bulcão¹,

Garcia²,

Limberger³

et al. 2012

Quím. Nova

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Recebido em 17/12/10; aceito em 12/7/11; publicado na web em 2/9/11 DESIGNER DRUGS: ANALYTICAL AND BIOLOGICAL ASPECTS. In the recent years, analytical toxicologists have been facing difficulties in detecting designer drugs due to the chemical modifications on the existing structures and the speed in which they are released into the market, requiring the development and improvement of specific and appropriate analytical methods. This work is a review of the literature which summarizes the characteristics of the drugs and the analytical validated methods using conventional and unconventional matrices currently used for correct identification and quantification of the following classes of emerging drugs of abuse: derivatives of opiates, amphetamines, tryptamines, piperazines and cannabinoids.Keywords: biological matrices; drug abuse; toxicology. INTRODUÇÃOAs chamadas designer drugs (drogas planejadas, ou seja, aná-logos estruturais) estão entre as drogas de abuso mais utilizadas no Ocidente. Seus efeitos psicotrópicos específicos, que fundamentam sua utilização como drogas de abuso, são descritos como capacidade aumentada da comunicabilidade, empatia e autoconhecimento, o que distingue esta classe de compostos das substâncias estimulantes e alucinógenas propriamente ditas, que produzem estados de euforia e agitação e, alucinações visuais e auditivas, respectivamente. 1,2A utilização de substâncias psicoativas é antiga na história da civilização, as primeiras experiências humanas ocorreram por meio do consumo de plantas. A partir do século XIX, o homem isolou princípios ativos vegetais como morfina, cocaína e efedrina. Porém, foi no final do século passado, com o surgimento das anfetaminas, que uma substância psicoativa foi totalmente sintetizada em laboratório. Com o aparecimento das drogas sintéticas, nos anos 80, ocorreu a popularização das designer drugs. Essas drogas têm como característica essencial o fato de terem sido modificadas em laboratório, com o intuito de potencializar ou criar efeitos psicoativos ou evitar efeitos indesejáveis, além de burlar a legislação vigente. Além disto, a disponibilidade e a diminuição do custo tecnológico permitem que tais drogas sejam sintetizadas com facilidade em laboratórios clandestinos domésticos. [3][4][5] Nos anos 90, com a popularização da internet, houve uma enorme divulgação e distribuição das designer drugs. 5,6 Entretanto, foi na primeira década do século XXI que o número de novos usuários de substâncias ilícitas aumentou de forma significativa, com relatos da apreensão de diversas designer drugs em todo o mundo. 7,8As designer drugs mais utilizadas são os compostos anfetamíni-cos, tais como 3,4-metileno-dioxi-anfetamina (MDA), 3,4-metilenodioxi-metanfetamina (MDMA, ecstasy), p-metoxi-anfetamina (PMA) e p-metoxi-metanfetamina (PMMA). No Brasil, o uso recreacional tem sido constatado em vários pacientes que buscam tratamento nas clínicas de reabilitação, além de apreensões destas drogas, sendo, portanto, de grande relevância sua correta identificação e/ou quantific...

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Metabolism of the new designer drug α-pyrrolidinopropiophenone (PPP) and the toxicological detection of PPP and 4′-methyl-α-pyrrolidinopropiophenone (MPPP) studied in rat urine using gas chromatography-mass spectrometry

Cited by 80 publications

References 20 publications

In Vitro, in Vivo and In Silico Metabolic Profiling of α-Pyrrolidinopentiothiophenone, A Novel Thiophene Stimulant

In Vitro, in Vivo and In Silico Metabolic Profiling of α-Pyrrolidinopentiothiophenone, A Novel Thiophene Stimulant

IDENTIFICATION OF CYTOCHROME P450 ENZYMES INVOLVED IN THE METABOLISM OF 4′-Methyl-Α-Pyrrolidinopropiophenone, a NOVEL SCHEDULED DESIGNER DRUG, IN HUMAN LIVER MICROSOMES

Designer drugs: aspectos analíticos e biológicos

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