Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways

Bort, Roque; Macé, Katherine; Boobis, Alan R.; Gómez‐Lechón, M. José; Pfeifer, Andréa; Castell, José V.

doi:10.1016/s0006-2952(99)00167-7

Cited by 203 publications

(121 citation statements)

References 24 publications

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“…We have already shown that diclofenac metabolism does not cause inactivation of CYP2C9 (Masubuchi et al, 2001), a major isozyme involved in diclofenac 4Ј-hydroxylation (Leemann et al, 1993). In the present study, effects on other CYP2C forms, which have been suggested to be involved in diclofenac metabolism, CYP2C8 and CYP2C19 (Bort et al, 1999), were assessed by paclitaxel 6␣-hydroxylation activity and diazepam N-demethylation activity at a lower substrate concentration, respectively, and no clear time-dependent decrease in the activity was observed (data not shown).…”

Section: Resultssupporting

confidence: 60%

“…CYP3A4 and CYP2C9 are major P450 isozymes responsible for diclofenac 5-hydroxylation and 4Ј-hydroxylation, respectively (Leemann et al, 1993;Shen et al, 1999;Tang et al, 1999b), and only CYP3A4 was inactivated, implying involvement of diclofenac 5-hydroxylation in the generation of a reactive metabolite(s) to bind to CYP3A4. The inactivation required relatively high diclofenac concentrations, corresponding to the fact that diclofenac 5-hydroxylation is a high-K m reaction as compared with 4Ј-hydroxylation (Bort et al, 1999). Thus we further investigated the potential role of diclofenac 5-hydroxylation in the inactivation of CYP3A4.…”

Section: Masubuchi Et Almentioning

confidence: 99%

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Diclofenac-Induced Inactivation of CYP3A4 and Its Stimulation by Quinidine

Masubuchi¹,

Ose²,

Horie³

2002

Drug Metab Dispos

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ABSTRACT:Incubation of human liver microsomes with diclofenac in the presence of NADPH resulted in a decrease in testosterone 6␤-hydroxylation activity. The decrease in the activity followed time-and concentration-dependent kinetics, required oxidative metabolism, and was resistant to reduced glutathione, suggesting that diclofenac causes a mechanism-based inactivation of cytochrome P450 (P450) 3A4 (CYP3A4). The inactivation was reproduced by using microsomes from B-lymphoblastoid cell lines expressing CYP3A4 instead of human liver microsomes. No other monooxygenase activities measured as indexes of P450 enzymes; CYP2C8, CYP2C9, or CYP2C19 was inactivated by the same incubation procedure. Quinidine, a stimulant of CYP3A4-mediated diclofenac 5-hydroxylation, did not affect the inactivation of CYP3A4 assessed by testosterone 6␤-hydroxylation activity but accelerated the inactivation assessed by diazepam 3-hydroxylation activity. These results supported the idea that diclofenac 5-hydroxylation is involved in the inactivation of CYP3A4 and described for the first time a stimulation of mechanism-based inactivation attributable to CYP3A4 heterotropic cooperativity. Preincubation of human liver microsomes with 5-hydroxydiclofenac instead of diclofenac did not cause the inactivation of CYP3A4, suggesting that 5-hydroxydiclofenac is not a precursor of a postulated reactive metabolite that inactivates CYP3A4, and thus 5-hydroxylation step is critical to inactivation of CYP3A4.

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Section: Resultssupporting

confidence: 60%

Section: Masubuchi Et Almentioning

confidence: 99%

Diclofenac-Induced Inactivation of CYP3A4 and Its Stimulation by Quinidine

Masubuchi¹,

Ose²,

Horie³

2002

Drug Metab Dispos

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“…These results indicate that diclofenac induces apoptosis through inhibition of mitochondrial respiration. The results obtained in our assay system for diclofenac are reasonable taking into account the evidence that both diclofenac itself and its metabolites, including 5-hydroxydiclofenac, have cytotoxic effects (Bort et al, 1999).…”

Section: Discussionsupporting

confidence: 81%

Usefulness of <i>in vitro</i> combination assays of mitochondrial dysfunction and apoptosis for the estimation of potential risk of idiosyncratic drug induced liver injury

et al. 2016

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-Drug-induced liver injury (DILI) is one of the serious and frequent drug-related adverse events. This adverse event is a main reason for regulatory action pertaining to drugs, including restrictions in clinical indications and withdrawal from clinical trials or the marketplace. Idiosyncratic DILI especially has become a major clinical concern because of its unpredictable nature, frequent hospitalization, need for liver transplantation and high mortality. The estimation of the potential for compounds to induce idiosyncratic DILI is very difficult in non-clinical studies because the precise mechanism of idiosyncratic DILI is still unknown. Recently, many in vitro assays which indicate a possibility of the prediction of the idiosyncratic DILI have been reported. Among these, some in vitro assays focus on the effects of compounds on mitochondrial function and the apoptotic effects of compounds on human hepatocytes. In this study, we measured oxygen consumption rate (OCR) and caspase-3/7 activity as an endpoint of mitochondrial dysfunction and apoptosis, respectively, with human hepatocytes after treatment with compounds causing idiosyncratic DILI (troglitazone, leflunomide, ranitidine and diclofenac). Troglitazone and leflunomide decreased the OCR but did not affect caspase-3/7 activity. Ranitidine increased caspase-3/7 activity but did not affect the OCR. Diclofenac decreased the OCR and increased caspase-3/7 activity. Acetaminophen and ethanol, which are also hepatotoxicants but do not induce idiosyncratic DILI, did not affect the OCR or caspase-3/7 activity. These results indicate that a combination assay of mitochondrial dysfunction and apoptosis is useful for the estimation of potential risk of compounds to induce idiosyncratic DILI.

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“…Diclofenac is metabolized by the CYP enzymes 2C9 and 3A4, resulting in reactive metabolite(s) that bind to microsomal proteins [Naisbitt et al 2007;Bort et al 1999;Shen et al 1999]. Diclofenac-induced dose-and concentrationdependant liver injury has been demonstrated in rat hepatocytes [Kretzrommel and Boelsterli, 1993].…”

Section: Pharmacokinetic Changesmentioning

confidence: 99%

Drug-induced liver injury in older adults

Mitchell

Hilmer

2010

Therapeutic Advances in Drug Safety

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Drug-induced liver injury (DILI) is an important cause of hospitalisation and of medication deregistration. In old age, susceptibility to DILI is affected by changes in physiology and increased interindividual variability, compounded by an increased prevalence of disease and the frailty syndrome. While dose-related or predictable DILI reactions are often detected in preclinical trials, the occurrence of rare hypersensitivity or idiosyncratic reactions cannot be reliably predicted from preclinical studies or even by clinical trials. The limited participation of older adults in clinical trials means that the susceptibility of this population to DILI is largely unknown. Vigilance during clinical trials and postmarketing surveillance must be universally practised. A systematic approach should be taken to determine not only which medicines are hepatotoxic and should be removed from the market, but also the hepatotoxicity risks from marketed drugs to consumers with different characteristics, many of whom are older people.

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Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways

Cited by 203 publications

References 24 publications

Diclofenac-Induced Inactivation of CYP3A4 and Its Stimulation by Quinidine

Diclofenac-Induced Inactivation of CYP3A4 and Its Stimulation by Quinidine

Usefulness of <i>in vitro</i> combination assays of mitochondrial dysfunction and apoptosis for the estimation of potential risk of idiosyncratic drug induced liver injury

Drug-induced liver injury in older adults

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