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

Springer, Dietmar; Paul, Liane D.; Staack, Roland F.; Kræmer, Thomas; Maurer, Hans H.

doi:10.1124/dmd.31.8.979

Cited by 24 publications

(8 citation statements)

References 13 publications

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“…In contrast, CYP2C19 revealed a biphasic kinetic profile. This is in accordance with previous findings of our group (Springer et al, 2003d) where a biphasic kinetic profile of CYP2C19 had also been observed when studying 4Ј-hydroxylation of the MPBP analog MPPP. CYP2D6 and CYP2C19 turned out to have the highest affinity toward MPBP with apparent K m values markedly lower than the K m of CYP1A2 (Table 1), whereas the capacity of CYP1A2 was considerably higher than those of the other two isoenzymes.…”

Section: Discussionsupporting

confidence: 82%

Identification of Cytochrome P450 Enzymes Involved in the Metabolism of the New Designer Drug 4′-Methyl-α-pyrrolidinobutyrophenone

Peters

Meyer²,

Theobald³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The involvement of human hepatic cytochrome P450 (P450) isoenzymes in the metabolism of the new designer drug 4-methyl-␣-pyrrolidinobutyrophenone (MPBP) to 4-(hydroxymethyl)-␣-pyrrolidinobutyrophenone (HO-MPBP) was studied using insect cell microsomes with cDNA-expressed human P450s and human liver microsomes (HLM). Incubation samples were analyzed by liquid chromatography-mass spectrometry. Only CYP2D6, CYP2C19, and CYP1A2 were capable of catalyzing MPBP 4-hydroxylation. According to the relative activity factor approach, these enzymes accounted for 54, 30, and 16% of net clearance. At 1 M MPBP, the chemical inhibitors quinidine (CYP2D6), fluconazole (CYP2C19), and ␣-naphthoflavone (CYP1A2) reduced metabolite formation in pooled HLM by 83, 53, and 47%, respectively, and at 50 M MPBP by 41, 47, and 45%, respectively. In experiments with HLM from CYP2D6 and CYP2C19 poor metabolizers, HO-MPBP formation was found to be 78 and 79% lower in comparison with pooled HLM, respectively. From these data, it can be concluded that polymorphically expressed CYP2D6 is mainly responsible for MPBP hydroxylation.The cytochrome P450 (P450) family accounts for more than 90% of oxidative metabolic reactions of xenobiotics (Guengerich, 2005). The involvement of particular P450 enzymes in the biotransformation of a new chemical entity is usually thoroughly investigated before it can be marketed in order to assess the risk of increased side effects in poor metabolizer subjects and of drug-drug or drug-food interactions. However, such data are typically acquired for substances intended for therapeutic use, not for drugs of the illicit market.1-(4-Methylphenyl)-2-pyrrolidin-1-ylbutan-1-one [4Ј-methyl-␣-pyrrolidinobutyrophenone (MPBP)] is a new designer drug of the pyrrolidinophenone type. Together with 4Ј-methyl-␣-pyrrolidinobutyrophenone (Roesner et al., 1999;Springer et al., 2003c), 4Ј-methyl-␣-pyrrolidinopropiophenone (MPPP) (Roesner et al., 1999;Springer et al., 2002;Springer et al., 2003c) However, they may be expected to be very similar to those of pyrovalerone (4Ј-methyl-␣-pyrrolidinovalerophenone) due to their close structural relation to this drug. Pyrovalerone is a psychostimulant that acts by releasing dopamine and norepinephrine from the respective nerve terminals (Fauquet et al., 1976;Servin et al., 1978) and inhibits the reuptake of these neurotransmitters (Meltzer et al., 2006). The latter was also shown for PVP. In comparison with amphetamine, pyrovalerone reportedly has similar psychostimulant effects but less influence on motor function in animals and humans (Stille et al., 1963;Holliday et al., 1964;Heimann and Lukacs, 1965). Pyrovalerone had been studied as a therapeutic drug (Heinmann and Vetter, 1965;Goldberg et al., 1973;Soderholm et al., 1976) but was withdrawn from the market and scheduled as a controlled substance after reports of its intravenous abuse (Deniker et al., 1975). A similar pharmacological profile of the pyrrolidinophenones would clearly be in line with their abuse as stimulant designer drug...

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Section: Discussionsupporting

confidence: 82%

Identification of Cytochrome P450 Enzymes Involved in the Metabolism of the New Designer Drug 4′-Methyl-α-pyrrolidinobutyrophenone

Peters

Meyer²,

Theobald³

et al. 2007

Drug Metab Dispos

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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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confidence: 99%

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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“…The RAF approach (11,13,14,16,22,23) was used to correct recombinant CYP formation rates for native human liver enzyme activity and revealed that CYP2D6 accounted for 81 % of predicted total TFMPP hydroxylation clearance by all individual CYPs in pHLMs. CYP1A2 and CYP3A4 were responsible for only about 10 % each.…”

Section: Discussionmentioning

confidence: 99%

“…Apparent K m and Vmax values for single isoforms were estimated by nonlinear regression according to the Michaelis-Menten equation. A two site binding model was applied to the data of the HLM experiments (11,12). The kinetic data were estimated using GraphPad Prism 3.02 software (San Diego, CA).…”

Section: Enzyme Kinetic Studiesmentioning

confidence: 99%

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Influence du cytochrome P450 2D6 sur le métabolisme de la TFMPP (1-(3-trifluoro-méthylphenyl) pipérazine) : étude à l'aide de modèles in vitro et in vivo

et al. 2003

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RÉSUMÉ La connaissance des isoenzymes du cytochrome P450 (CYP), qui sont responsables du métabolisme des xénobiotiques, est indispensable pour prédire la toxicocinétique et Vévaluation des risques toxicologiques, MOTS-CLÉS : l-(3-trifluoro-méthyl-phényl)pipérazine, TFMPP, métabolis-me, cytochrome P450. rats Wistar, rats Dark Agouti. SUMMARY Knowledge of the cytochrome P450 (CYP) isoenzymes responsible for the metabolism of xenobiotics is indispensable for prediction of toxicokinetics and for risk assessment. l-(3-trifluoro-methyl-phenyl)piperazine (TFMPP) is a new designer drug. Previous studies had shown that TFMPP was mainly metabolized by aromatic hydroxylation to hydroxy TFMPP (HO-TFMPP

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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

Cited by 24 publications

References 13 publications

Identification of Cytochrome P450 Enzymes Involved in the Metabolism of the New Designer Drug 4′-Methyl-α-pyrrolidinobutyrophenone

Identification of Cytochrome P450 Enzymes Involved in the Metabolism of the New Designer Drug 4′-Methyl-α-pyrrolidinobutyrophenone

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

Influence du cytochrome P450 2D6 sur le métabolisme de la TFMPP (1-(3-trifluoro-méthylphenyl) pipérazine) : étude à l'aide de modèles in vitro et in vivo

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