Pharmacology, Clinical Efficacy, and Adverse Effects of the Nonsteroidal Anti‐Inflammatory Agent Benoxaprofen

Dahl, Stephen L.; Ward, John

doi:10.1002/j.1875-9114.1982.tb03212.x

Cited by 22 publications

(16 citation statements)

References 25 publications

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“…It should be noted that the glucuronidation biotransformation of the ( S )-PZQ phase I metabolites was greater than for the ( R )-PZQ phase I metabolites, which might explain why ( R )-PZQ exhibited enhanced therapeutic activity in vivo . Some studies have reported the side-effects produced by active glucuronides [33–36], such as the withdrawal of benoxaprofen from world markets [37], which mainly resulted from toxicity related to hepatic metabolism via glucuronidation and the correlation between glucuronide covalent binding with proteins to the risk of idiosyncratic drug toxicity (IDT) [38]. Although the glucuronides of PZQ detected are not acyl glucuronides, the possibility of active glucuronides being generated should also be considered in the future studies of PZQ toxicity.…”

Section: Discussionmentioning

confidence: 99%

Metabolic profiling of praziquantel enantiomers

Wang

Fang

Zheng

et al. 2014

Biochemical Pharmacology

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Praziquantel (PZQ), prescribed as a racemic mixture, is the most readily available drug to treat schistosomiasis. In the present study, ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) based metabolomics was employed to decipher the metabolic pathways and enantioselective metabolic differences of PZQ. Many phase I and four new phase II metabolites were found in urine and feces samples of mice 24h after dosing indicating that the major metabolic reaction encompassed oxidation, dehydrogenation, and glucuronidation. Differences in the formation of all these metabolites were observed between (R)-PZQ and (S)-PZQ. In an in vitro phase I incubation system, the major involvement of CYP3A, CYP2C9, and CYP2C19 in the metabolism of PZQ, and CYP3A, CYP2C9, and CYP2C19 exhibited different catalytic activity towards the PZQ enantiomers. Apparent Km and Vmax differences were observed in the catalytic formation of three mono-oxidized metabolites by CYP2C9 and CYP3A4 further supporting the metabolic differences for PZQ enantiomers. Molecular docking showed that chirality resulted in differences in location and conformation, which likely accounts for the metabolic differences. In conclusion, in silico, in vitro, and in vivo methods revealed the enantioselective metabolic profile of praziquantel.

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Section: Discussionmentioning

confidence: 99%

Metabolic profiling of praziquantel enantiomers

Wang

Fang

Zheng

et al. 2014

Biochemical Pharmacology

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“…Hepatotoxicity in elderly patients reported for BNX was the cause of its withdrawal from the world market (Dahl and Ward, 1982). The liver was also found to be a tissue targeted by both BNX and FLX in vivo in rats (Dong et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…BNX was marketed as a racemic mixture, whereas FLX was marketed as the S-isomer only. Several reports of fatal cholestatic jaundice, often associated with nephrotoxicity, led to the withdrawal of BNX from the world market only 5 months after its launch (Dahl and Ward, 1982). However, no fatal adverse events related to FLX have been reported.…”

mentioning

confidence: 99%

Glucuronidation and Covalent Protein Binding of Benoxaprofen and Flunoxaprofen in Sandwich-Cultured Rat and Human Hepatocytes

Dong

Smith²

2009

Drug Metab Dispos

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ABSTRACT:Benoxaprofen (BNX), a nonsteroidal anti-inflammatory drug (NSAID) that was withdrawn because of hepatotoxicity, is more toxic than its structural analog flunoxaprofen (FLX) in humans and rats. Acyl glucuronides have been hypothesized to be reactive metabolites and may be associated with toxicity. Both time-and concentration-dependent glucuronidation and covalent binding of BNX, FLX, and ibuprofen (IBP) were determined by exposing sandwich-cultured rat hepatocytes to each NSAID. The levels of glucuronide and covalent protein adduct measured in cells followed the order BNX > FLX > IBP. These results indicate that 1) BNXglucuronide (G) is more reactive than FLX-G, and 2) IBP-G is the least reactive metabolite, which support previous in vivo studies in rats. The proportional increases of protein adduct formation for BNX, FLX, and IBP as acyl glucuronidation increased also support the hypothesis that part of the covalent binding of all three NSAIDs to hepatic proteins is acyl glucuronide-dependent. Moreover, theses studies confirmed the feasibility of using sandwich-cultured rat hepatocytes for studying glucuronidation and covalent binding to hepatocellular proteins. These studies also showed that these in vitro methods can be applied using human tissues for the study of acyl glucuronide reactivity. More BNX-protein adduct was formed in sandwich-cultured human hepatocytes than FLX-protein adduct, which not only agreed with its relative toxicity in humans but also was consistent with the in vitro findings using rat hepatocyte cultures. These data support the use of sandwich-cultured human hepatocytes as an in vitro screening model of acyl glucuronide exposure and reactivity.Many types of acidic drugs form acyl glucuronides, and other xenobiotics are metabolized to carboxylic acids (Phase I metabolites), which subsequently undergo Phase II conjugation to form acyl glucuronides. Often such a glucuronide conjugate constitutes the major metabolite. The major site of conjugation for most compounds in humans is believed to be the liver. Modification of critical hepatic proteins by covalent binding of acidic drugs through reactive acyl glucuronides may provide a basis for direct hepatocyte toxicity or immune-mediated adverse reactions (Gillette, 1974;Faed, 1984;Boelsterli, 2002;Bailey and Dickinson, 2003).Some pharmaceutical companies have been conducting in vitro experiments by incubating acyl glucuronides with model proteins or peptides (Wang et al., 2004) to determine their reactivity, and hence possibly predict the relative extent of covalent protein binding in vivo in humans. This method requires chemical synthesis or biosynthesis of individual glucuronides for each drug candidate, a process that can be tedious and costly. In addition, hepatic tissue proteins are not present in the incubation, which makes it less likely to correlate covalent protein binding with hepatotoxicity. In vitro models involving hepatic materials, including liver homogenates, microsomal subcellular preparation, and isolated hepatocyte s...

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“…The produced covalent protein adducts increase the risk of idiosyncratic drug toxicity (IDT) including a wide range of adverse drug effects such as drug hypersensitivity reactions and cellular toxicity [39]. As a result of this metabolic pathway and its biological consequences, a number of nonsteroidal anti-inflammatory drugs cause adverse reactions in humans, as exemplified by benoxaprofen [40]. In the case of UGTs being induced or in kidney disease, the toxic glucuronides will accumulate and this will increase the risk of IDT.…”

Section: Concentration Spiked (M)mentioning

confidence: 99%