Cytochrome P450-Catalyzed Oxidation of Halobenzene Derivatives

Rietjens, Ivonne M. C. M.; Besten, C. den; Hanzlik, Robert P.; Bladeren, P.J. van

doi:10.1021/tx9601061

Cited by 70 publications

(68 citation statements)

References 50 publications

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“…The exact structures of the glutathione conjugates could not be determined from the mass spectral data. The conjugates were postulated to be formed by oxidative defluorination of the trifluoro-phenyl ring and addition of reduced glutathione, as described in the literature (Rietjens et al, 1997;Park et al, 2001).…”

Section: Beconi Et Almentioning

confidence: 99%

“…A mixture of glutathione conjugates (Fig. 1) speculated to have been formed by epoxidation of the trifluorophenyl ring, followed by addition of reduced glutathione and loss of fluoride (Rietjens et al, 1997;Park et al, 2001) appeared to be rat-specific, in that they were not detected in humans or dogs. Another interesting species difference was the relative abundance of M2 and M5 in dog plasma especially at the later time points (ϳ33 and 56% of the plasma radioactivity at 7 and 24 h, respectively), even though a similar fraction of the dose, less than 5%, was eliminated as M2 and M5 in all species.…”

Section: Downloaded Frommentioning

confidence: 99%

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Disposition of the Dipeptidyl Peptidase 4 Inhibitor Sitagliptin in Rats and Dogs

Beconi¹,

Reed²,

Teffera³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The pharmacokinetics, metabolism, and excretion of sitagliptin The plasma clearance and volume of distribution of sitagliptin were higher in rats (40-48 ml/min/kg, 7-9 l/kg) than in dogs (ϳ9 ml/min/kg, ϳ3 l/kg), and its half-life was shorter in rats, ϳ2 h compared with ϳ4 h in dogs. Sitagliptin was absorbed rapidly after oral administration of a solution of the phosphate salt. The absolute oral bioavailability was high, and the pharmacokinetics were fairly dose-proportional. After administration of [ 14 C]sitagliptin, parent drug was the major radioactive component in rat and dog plasma, urine, bile, and feces. Sitagliptin was eliminated primarily by renal excretion of parent drug; biliary excretion was an important pathway in rats, whereas metabolism was minimal in both species in vitro and in vivo. Approximately 10 to 16% of the radiolabeled dose was recovered in the rat and dog excreta as phase I and II metabolites, which were formed by N-sulfation, N-carbamoyl glucuronidation, hydroxylation of the triazolopiperazine ring, and oxidative desaturation of the piperazine ring followed by cyclization via the primary amine. The renal clearance of unbound drug in rats, 32 to 39 ml/min/kg, far exceeded the glomerular filtration rate, indicative of active renal elimination of parent drug.Dipeptidyl peptidase 4 (DPP-4) is a ubiquitous proline-specific serine protease responsible for the rapid inactivation of the incretin glucagon-like peptide 1 (GLP-1) (Mentlein et al., 1993;Gorrell, 2005). GLP-1 and GLP-1 analogs have been shown to decrease fasting and postprandial glucose in diabetic patients when given as a continuous intravenous infusion or by subcutaneous administration (Zander et al., 2002;Gautier et al., 2005). The effectiveness of orally administered DPP-4 inhibitors has been demonstrated in obese Zucker rats (Balkan et al., 1999;Pospisilik et al., 2002), mice (Mu et al., 2006, and humans (Ahren et al., 2004;Herman et al., 2004Herman et al., , 2005aScott et al., 2005;Cornell, 2006). Thus, stabilization of GLP-1 via DPP-4 inhibition represents a new therapeutic approach for type 2 diabetes (Drucker, 2006;Green et al., 2006).Sitagliptin ( (Fig. 1), is a potent and selective, reversible inhibitor of DPP-4 with an IC 50 value of 18 nM (Kim et al., 2005). Sitagliptin has been shown to inhibit plasma DPP-4 activity in normal volunteers (Herman et al., 2005a;Bergman et al., 2006) and in patients with type 2 diabetes (Herman et al., 2004), and to significantly reduce HbA 1c and fasting plasma glucose in patients with type 2 diabetes (Herman et al., 2005b;Scott et al., 2005). In support of the suitability of the rat and dog as toxicology species, the disposition of sitagliptin was evaluated in these species and compared with that in humans. Results from in vitro (rat, dog, human) and in vivo studies in rats and dogs are discussed herein. The absorption, metabolism, and excretion of sitagliptin in humans are reported in the accompanying article . Materials and MethodsChemicals and Reagents. Sitagliptin was prep...

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Section: Beconi Et Almentioning

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

Disposition of the Dipeptidyl Peptidase 4 Inhibitor Sitagliptin in Rats and Dogs

Beconi¹,

Reed²,

Teffera³

et al. 2007

Drug Metab Dispos

View full text Add to dashboard Cite

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“…CYP-Mediated Bioactivation of Inhaled Anesthetics an electrophilic epoxide intermediate [55]. Certainly, this is the mechanism underlying the toxicity of the organic solvents benzene and bromobenzene [70] [71]. Likewise, avoiding structural alerts altogether can lead to missing out on potentially important medicines, ultimately beneficial to humanity.…”

Section: Bioactivation Of the Calcium-channel Opener Maxipost In Rat mentioning

confidence: 99%

Structural Alerts, Reactive Metabolites, and Protein Covalent Binding: How Reliable Are These Attributes as Predictors of Drug Toxicity?

Kalgutkar

Didiuk

2009

Chemistry & Biodiversity

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In an increasing number of cases, a deeper understanding of the biochemical basis for idiosyncratic adverse drug reactions (IADRs) has aided to replace a vague perception of a chemical class effect with a sharper picture of individual molecular peculiarity. Considering that IADRs are too complex to duplicate in a test tube, and their idiosyncratic nature precludes prospective clinical studies, it is currently impossible to predict which new drugs will be associated with a significant incidence of toxicity. Because it is now widely appreciated that reactive metabolites, as opposed to the parent molecules from which they are derived, are responsible for the pathogenesis of some IADRs, the propensity of drug candidates to form reactive metabolites is generally considered a liability. Procedures have been implemented to monitor reactive-metabolite formation in discovery with the ultimate goal of eliminating or minimizing the liability via rational structural modification of the problematic chemical series. While such mechanistic studies have provided retrospective insight into the metabolic pathways which lead to reactive metabolite formation with toxic compounds, their ability to accurately predict the IADR potential of new drug candidates has been challenged. There are several instances of drugs that form reactive metabolites, but only a fraction thereof cause toxicity. This review article will outline current approaches to evaluate bioactivation potential of new compounds with particular emphasis on the advantages and limitation of these assays. Plausible reason(s) for the excellent safety record of certain drugs susceptible to bioactivation will also be explored and should provide valuable guidance in the use of reactive-metabolite assessments when nominating drug candidates for development.

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“…Cytochromes P450 mediated oxidation of HCB can result in the formation of electrophilic intermediates such as epoxides and/or benzoquinones, which can covalently bind with proteins and DNA (Rietjens et al, 1997). In a study to test the DNA-binding of HCB, untreated or phenobarbital pre-treated male Wistar rats were administered 25 mg/kg radiolabelled HCB in refined peanut oil for 24 hours (Gopalaswamy and Nair, 1992).…”

Section: Genotoxicitymentioning

confidence: 99%

“…Three distinct pathways appear to operate in mammals ( Figure 3): oxidation which gives rise to phenolic metabolites including pentachlorophenol, tetrachlorohydroquinone and tetrachlorobenzoquinone; glutathione-conjugation with loss of chlorine leading to corresponding cysteine conjugate, then to mercapturic acids, and finally to pentachlorobenzenethiol, pentachlorothioanisole and other sulfur-containing metabolites; a minor reductive dechlorination pathway that yields less chlorinated benzenes (Renner, 1988;WHO-IPCS, 1997). The oxidative attack on HCB, mediated by cytochrome P-450 monooxygenases, results in the formation of an electrophilic intermediate, typically an epoxide that covalently interacts with tissue macromolecules (Van Ommen et al, 1985, Rietjens et al, 1997. Alternative pathways that compete for interaction with the epoxide, include spontaneous isomerization of the epoxide to a phenol, epoxide hydrolase-catalyzed conversion of the epoxide to a dihydrodiol, and either spontaneous or glutathione-S-transferase-mediated conjugation of epoxides with glutathione.…”

Section: Metabolismmentioning

confidence: 99%

Opinion of the Scientific Panel on contaminants in the food chain [CONTAM] related to Hexachlorobenzene as undesirable substance in animal feed

2006

EFSA Journal

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Cytochrome P450-Catalyzed Oxidation of Halobenzene Derivatives

Cited by 70 publications

References 50 publications

Disposition of the Dipeptidyl Peptidase 4 Inhibitor Sitagliptin in Rats and Dogs

Disposition of the Dipeptidyl Peptidase 4 Inhibitor Sitagliptin in Rats and Dogs

Structural Alerts, Reactive Metabolites, and Protein Covalent Binding: How Reliable Are These Attributes as Predictors of Drug Toxicity?

Opinion of the Scientific Panel on contaminants in the food chain [CONTAM] related to Hexachlorobenzene as undesirable substance in animal feed

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