First evidence that cytochrome P450 may catalyze both S-oxidation and epoxidation of thiophene derivatives

Dansette, Patrick M.; Bertho, Gildas; Mansuy, Daniel

doi:10.1016/j.bbrc.2005.08.091

Cited by 86 publications

(77 citation statements)

References 32 publications

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“…Although we could not definitely characterize the incorporated position of GSH and oxygen at the thiophene ring, another GSH conjugate (B2, isomer of B1) was also detected. Dansette et al (2005) reported interesting MS/MS fragment analyses on the two GSH conjugates of 2-phenylthiophene, in which the loss of 48 amu (sulfoxide) was favored over the loss of 18 amu (water) in the case of the GSH conjugate of the thiophene S-oxide, whereas the loss of 18 amu was dominant in the case of 5-hydroxy-4-glutathionyl-4,5-dihydrothiophene resulting from the addition of GSH to the thiophene epoxide. However, another thiophene GSH adduct of S-oxide showed no loss of 48 amu but did show a loss of 18 amu in the product ion spectrum (Medower et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Ticlopidine in Rats: Identification of the Main Biliary Metabolite as a Glutathione Conjugate of Ticlopidine S-Oxide

Shimizu¹,

Atsumi²,

Nakazawa³

et al. 2009

Drug Metabolism and Disposition

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ABSTRACT:We have identified several novel metabolites of ticlopidine, a well known antiplatelet agent and have revealed its metabolic route in rats. The main biliary metabolite of ticlopidine was characterized as a glutathione (GSH) conjugate of ticlopidine S-oxide, in which conjugation had occurred at carbon 7a in the thienopyridine moiety. Quantitative analysis revealed that 29% of the dose was subjected to the formation of reactive intermediates followed by conjugation with GSH after oral administration of ticlopidine (22 mg/ kg) to rats. In vitro incubation of ticlopidine with rat liver 9000g supernatant fraction (S9) fractions led to the formation of multiple metabolites, including 2-oxo-ticlopidine, the precursor for the pharmacologically active ticlopidine metabolite, [1-(2-chlorobenzyl)-4-mercaptopiperidin-(3Z)-ylidene] acetic acid. A novel thiophene ring-opened metabolite with a thioketone group and a carboxylic acid moiety has also been detected after incubation of 2-oxo-ticlopidine with rat liver microsomes or upon incubation of ticlopidine with rat liver S9 fractions.Ticlopidine is a well known antiplatelet agent (Quinn and Fitzgerald, 1999) and has been widely used for the secondary prevention of atherothrombosis (Jacobson, 2004). The metabolism of ticlopidine is complex because of extensive oxidation in the liver (Saltiel and Ward, 1987). For example, less than 1% of the parent compound was detected in urine, whereas approximately 60 and 25% of radioactivity was recovered in urine after a single oral administration of [ 14 C]ticlopidine to humans (Noble and Goa, 1996) and rats (Tuong et al., 1981), respectively. Furthermore, a large difference was observed between the total radioactivity and unchanged ticlopidine level in the plasma (Panak et al., 1983). In the 1980s, metabolic studies suggested that N-dealkylation, N-oxidation, and oxidation of the thiophene ring followed by ring opening appeared to be the main routes, but numerous highly polar urinary and biliary metabolites in both humans and animals remained unidentified (Tuong et al., 1981;Panak et al., 1983). More recently, novel ticlopidine metabolites such as the S-oxide form (Ha-Duong et al., 2001) and the pharmacologically active metabolite (Yoneda et al., 2004) have been detected. However, the whole metabolism of ticlopidine has remained unclarified.In the present study, we have identified several novel metabolites of ticlopidine and revealed the metabolic pathways of ticlopidine quantitatively. Moreover, an in vitro experiment was conducted to elucidate the whole metabolic route of ticlopidine including the biotransformation to the pharmacologically active metabolite.

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Section: Discussionmentioning

confidence: 99%

Metabolism of Ticlopidine in Rats: Identification of the Main Biliary Metabolite as a Glutathione Conjugate of Ticlopidine S-Oxide

Shimizu¹,

Atsumi²,

Nakazawa³

et al. 2009

Drug Metabolism and Disposition

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“…The incorporation of 18 O into the 5-hydroxythiophene metabolite indicated an epoxide intermediate pathway (Dalvie et al, 2002;O'Donnell et al, 2003). Furthermore, in the study of bioactivation of 2-phenylthiophene by rat liver microsomes in the pres- ence of GSH, a metabolite was isolated and identified as the product of GSH nucleophilic attack to the 4,5-epoxide of 2-phenylthiophene (Dansette et al, 2005). This provided direct evidence for the epoxidation pathway in thiophene metabolic activation.…”

Section: Discussionmentioning

confidence: 88%

“…The S-oxidation and epoxidation mechanisms have been widely accepted for the metabolic activation for thiophene derivatives. The S-oxidation mechanism was supported by evidence of the formation of thiophene S-oxide in vitro and in vivo or its 1,4-Michael addition product or sulfoxide dimers from the DielsAlder dimerization (Dansette et al, 2005;Medower et al, 2008). The epoxidation mechanism is supported by indirect evidence with bioactivation of 2-(4-methoxybenzoyl)thiophene in the presence of 18 O 2 .…”

Section: Discussionmentioning

confidence: 91%

“…The metabolic activation mechanism is known to be determined by the structure and substitution pattern on the thiophene ring. For example, the thiophene moiety from TA and suprofen undergoes S-oxidation (Dansette et al, 1992(Dansette et al, , 2005O'Donnell et al, 2003;Medower et al, 2008) or thiophene ring epoxidation (O'Donnell, 2003;Dansette et al, 2005), followed by nucleophilic attack on the thiophene ring and deoxygenation or dehydration to form protein adducts or GSH conjugates (Fig. 9).…”

Section: Discussionmentioning

confidence: 99%

“…At the same time, both drugs inactivate CYP2C enzymes (López-Garcia et al, 1994;Jean et al, 1996;O'Donnell et al, 2003;Masubuchi and Horie, 2007;Hutzler et al, 2009). The metabolic activation of thiophene derivatives has been suggested to occur via sulfur oxidation or an epoxidation mechanism (Dansette et al, 1992(Dansette et al, , 2005Valadon et al, 1996;O'Donnell et al, 2003;Medower et al, 2008). The resulting toxicities of thiophenes are thought to be related to the formation of these reactive metabolites.…”

Section: Introductionmentioning

confidence: 99%

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Novel Metabolic Bioactivation Mechanism for a Series of Anti-Inflammatory Agents (2,5-Diaminothiophene Derivatives) Mediated by Cytochrome P450 Enzymes

Yang²,

Shilliday³

et al. 2010

Drug Metabolism and Disposition

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ABSTRACT:The thiophene moiety is considered a structural alert in molecular design in drug discovery, largely because several thiophene-containing drugs, including tienilic acid and suprofen, have been withdrawn from the market because of toxicities. Reactive thiophene intermediates, activated via sulfur oxidation or ring epoxidation, are possible culprits for these adverse side effects. In this work, the metabolic activation of an anti-inflammatory agent, 1-(3-carbamoyl-5-(2,3,5-trichlorobenzamido)thiophen-2-yl)urea), containing a 2,5-diaminothiophene structure, was studied in liver microsomes in the presence of glutathione or N-acetylcysteine as trapping agents. In addition, the glutathione conjugate was detected in bile from a bile duct-cannulated rat study. The structure of the glutathione conjugate was identified by mass spectrometry and 1 H NMR. The glutathione molecule was attached to the thiophene ring, replacing the existing proton. Metabolic phenotyping experiments, using chemical inhibitors or recombinant cytochromes P450 (P450), demonstrated that CYP3A4 was the major P450 enzyme responsible for the metabolic activation, followed by CYP1A2, 2Cs, and 2D6. A novel metabolic activation mechanism is proposed whereby the 2,5-diaminothiophene moiety undergoes oxidation to a 2,5-diimine thiophene reactive intermediate. This mechanism was used to support efforts to eliminate reactive metabolite generation via structural modification of ring substituents using structure-activity relationships. The disruption of formation of the 2,5-diimine reactive intermediate resulted in the elimination of glutathione conjugate formation both in vitro and in vivo and provided a rational approach to mitigating potential safety risks associated with this class of thiophenes in drug research and development.

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Principles of Drug Metabolism

Dalvie

Testa

2021

Burger's Medicinal Chemistry and Drug Discovery

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Metabolism is a complex process that involves enzymatic modification of drugs and xenobiotics and is one of the most important determinants of their fate in the body. Although the drug metabolism is considered a process of detoxification, the products of metabolism can play an important role in the pharmacology and toxicology of the parent drug. Studying the metabolism of newly synthesized molecules is a valuable strategy that allows one to identify the underlying problems, such as “soft spots,” or metabolic activation, that affect the systemic exposure of a molecule and safety and efficacy. Early investigative metabolism of new compounds has helped in assessing the bioactivation potential of these candidates and thus, avoid reactive metabolites or put mitigation strategies in place. Metabolism can also lead to pharmacologically active metabolites. These metabolites can have superior pharmacological, pharmacokinetic, and safety profiles compared to their parent drug and can therefore be developed as drugs. This chapter provides an overview of the enzymes involved in the metabolism of xenobiotics and the different metabolic pathways. An attempt has been made to illustrate these principles with pertinent example with a brief review of topics of potential interests to aspiring medicinal chemists namely, the factors that may influence biotransformation or applications to predict the sites of metabolism. While the medicinal chemists are not expected to possess a deep knowledge of the mechanistic aspects, the hope is that the principles outlined in this chapter will assist them in designing a better drug.

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First evidence that cytochrome P450 may catalyze both S-oxidation and epoxidation of thiophene derivatives

Cited by 86 publications

References 32 publications

Metabolism of Ticlopidine in Rats: Identification of the Main Biliary Metabolite as a Glutathione Conjugate of Ticlopidine S-Oxide

Metabolism of Ticlopidine in Rats: Identification of the Main Biliary Metabolite as a Glutathione Conjugate of Ticlopidine S-Oxide

Novel Metabolic Bioactivation Mechanism for a Series of Anti-Inflammatory Agents (2,5-Diaminothiophene Derivatives) Mediated by Cytochrome P450 Enzymes

Principles of Drug Metabolism

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