IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-<i>N</i>-[[(4-TRIFLUOROMETHYL)-PHENYL] METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. II. IDENTIFICATION OF METABOLITES BY LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY

Liu, David Q.; Karanam, Bindhu V.; Doss, George A.; Sidler, Rick; Vincent, Stella; Hop, Cornelis E. C. A.

doi:10.1124/dmd.104.000059

Cited by 20 publications

(18 citation statements)

References 13 publications

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“…A combination of other MS-based techniques, such as stable isotope labeling, accurate mass measurements, and H/D exchange, may help to further narrow possible metabolite structures. When MS analysis fails to provide the absolute identification of the metabolites, LC-NMR should be considered [64][65][66].…”

Section: Metabolite Characterization In Drug Discovery Settingsmentioning

confidence: 99%

Application of Mass Spectrometry for Metabolite Identification

Ma¹,

Chowdhury²,

Alton³

2006

CDM

144

100

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Metabolism studies play a pivotal role in drug discovery and development. Characterization of metabolic "hot-spots" as well as reactive and pharmacologically active metabolites is critical to designing new drug candidates with improved metabolic stability, toxicological profile and efficacy. Metabolite identification in the preclinical species used for safety evaluation is required in order to determine whether human metabolites have been adequately tested during non-clinical safety assessment. From an instrumental standpoint, high performance liquid chromatography (HPLC) coupled with mass spectrometry (MS) dominates all analytical tools used for metabolite identification. The general strategies employed for metabolite identification in both drug discovery and drug development settings together with sample preparation techniques are reviewed herein. These include a discussion of the various ionization methods, mass analyzers, and tandem mass spectrometry (MS/MS) techniques that are used for structural characterization in a modern drug metabolism laboratory. Mass spectrometry-based techniques, such as stable isotope labeling, on-line H/D exchange, accurate mass measurement to enhance metabolite identification and recent improvements in data acquisition and processing for accelerating metabolite identification are also described. Rounding out this review, we offer additional thoughts about the potential of alternative and less frequently used techniques such as LC-NMR/MS, CRIMS and ICPMS.

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Section: Metabolite Characterization In Drug Discovery Settingsmentioning

confidence: 99%

Application of Mass Spectrometry for Metabolite Identification

Ma¹,

Chowdhury²,

Alton³

2006

CDM

144

100

View full text Add to dashboard Cite

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“…Moreover, S‐oxidation of the TZD ring of troglitazone21 and MK0767 (V. Reddy et al, in preparation) has been implicated in the ring scission observed to occur enzymatically under oxidative conditions. In nonclinical species and humans, the major metabolism pathway for MK‐0767 is believed to proceed via S‐oxidation followed by TZD cleavage and reduction and further methylation and oxidation 22, 23…”

Section: Resultsmentioning

confidence: 99%

Enantiomer ratio of MK‐0767 in humans and nonclinical species

Shen

Bakhtiar

Komuro

et al. 2005

Rapid Comm Mass Spectrometry

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MK-0767, (+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]methyl]benzamide, is a thiazolidinedione-containing dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist that has been studied as a potential treatment for patients with type 2 diabetes. MK-0767 contains a chiral center at the C-5 position of the thiazolidinedione ring and was being developed as the racemate, due to the rapid interconversion of its enantiomers in biological samples. In the present work the in vitro and in vivo concentration ratios of the (+)-(R) to (-)-(S) enantiomers of MK-0767 were determined in plasma from humans (in vitro only) and nonclinical species used in the toxicological evaluation of rac-MK-0767, namely CD-1 mice, Sprague-Dawley rats, beagle dogs, New Zealand white rabbits, and rhesus monkeys. The R/S ratio was determined by chiral liquid chromatography/tandem mass spectrometry. Species differences were observed in the in vitro and in vivo enantiomeric ratios, as well as differences between in vitro and in vivo in some species. The in vitro R/S ratio was similar in dogs and humans (approximately 1.5-1.7). In rats and monkeys, the ratio was approximately unity, both in vitro and in vivo. In mice, the ratio was higher in vitro (approximately 1) than in vivo (approximately 0.6), while in rabbits it was higher in vivo (approximately 1) than in vitro (approximately 0.5). These results suggested that differential binding of the MK-0767 enantiomers to plasma and tissue proteins and other macromolecules may be affecting the R/S ratio both in vitro and in vivo, since in protein-free systems MK-0767 exists as the racemate.

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“…7,8 The S-oxidation-based ringopened metabolites were also reported by Liu and co-workers, where they emphasized the formation of these metabolites via oxidative cleavage of the TZD ring by S-oxidation. 9 Reddy et al studied the mechanism of metabolic scission of the TZD ring, highlighting the importance of the initial S-oxidation step. 10 Baughman et al reported the CYP3A4-mediated metabolic activation of PGZ in human and rat liver microsomes and hepatocytes, and stressed various ring-opened reactive intermediates and conjugation with glutathione.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Flosequinan and its sulfone metabolite possess vasodilatation, inotropic, and hemodynamic properties, and are useful in acute heart failure . On the other hand, the S -oxidation of thiazolidinedione ( TZD ) ring in the glitazone class of antidiabetic drugs leads to TZD ring-opening followed by several toxicological consequences. − …”

Section: Introductionmentioning

confidence: 99%

Density Functional Study on the Cytochrome-Mediated S-Oxidation: Identification of Crucial Reactive Intermediate on the Metabolic Path of Thiazolidinediones

2012

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S-Oxidation is an important cytochrome P450 (CYP450)-catalyzed reaction, and the structural and energetic details of this process can only be studied by using quantum chemical methods. Thiazolidinedione (TZD) ring metabolism involving initial S-oxidation leads to the generation of reactive metabolites (RMs) and subsequent toxicity forcing the withdrawal of the glitazone class of drugs, thus, the study of the biochemical pathway of TZD ring metabolism is a subject of interest. The S-oxidation of the TZD ring and the formation of the isocyanate intermediate (ISC) was implicated as a possible pathway; however, there are several questions still unanswered in this biochemical pathway. The current study focuses on the CYP450-mediated S-oxidation, fate of the sulfoxide product (TZDSO), ring cleavage to ISC, and formation of nucleophilic adducts. The process of S-oxidation was explored by using Cpd I (iron(IV)-oxo porphyrin, to mimic CYP450) at TZVP/6-311+G(d) basis set. The barriers were calculated after incorporating dispersion and solvent corrections. The metabolic conversion from TZDSO to ISC (studied at B3LYP/6-311++G(2df,3pd)//B3LYP/6-31+G(d)) required a novel protonated intermediate, TZDSOH(+). The effect of higher basis sets (6-311+G(d,p), aug-cc-pvqz) on this conversion was studied. TZDSOH(+) was observed to be more reactive and thermodynamically accessible than ISC, indicating that TZDSOH(+) is the actual reactive intermediate leading to toxicity of the TZD class of compounds.

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IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL)-PHENYL] METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. II. IDENTIFICATION OF METABOLITES BY LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY

Cited by 20 publications

References 13 publications

Application of Mass Spectrometry for Metabolite Identification

Application of Mass Spectrometry for Metabolite Identification

Enantiomer ratio of MK‐0767 in humans and nonclinical species

Density Functional Study on the Cytochrome-Mediated S-Oxidation: Identification of Crucial Reactive Intermediate on the Metabolic Path of Thiazolidinediones

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