Studies to Further Investigate the Inhibition of Human Liver Microsomal CYP2C8 by the Acyl-β-Glucuronide of Gemfibrozil

Jenkins, Susan; Zvyaga, Tatyana; Johnson, Simon R.; Hurley, J.; Wagner, Andrew J.; Burrell, Richard C.; Turley, Wesley A.; Leet, John E.; Philip, Thomas; Rodrigues, A. David

doi:10.1124/dmd.111.041947

Cited by 23 publications

(27 citation statements)

References 20 publications

(24 reference statements)

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“…The in vivo consequences of the inhibitory effects of these metabolites are discussed in section VI. In an in vitro study by Jenkins et al (2011), the acyl glucuronides of atorvastatin, dehydroketoprofen, diclofenac, ibuprofen, indomethacin, rac-ketoprofen, mefenamic acid, R-and S-naproxen, and simvastatin did not affect CYP2C8 by metabolism-dependent inhibition.…”

Section: B Metabolism-dependent Inhibitionmentioning

confidence: 92%

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Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

et al. 2015

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Section: B Metabolism-dependent Inhibitionmentioning

confidence: 92%

“…The benzylic oxidation of the glucuronide by CYP2C8 leads to haem alkylation and irreversible inactivation of CYP2C8 (Baer et al, 2009;Jenkins et al, 2011). In HLM, the k inact value of CYP2C8 by gemfibrozil 1-O-b-glucuronide has been 0.21 1/min and K I 20-52 mM (Ogilvie et al, 2006).…”

Section: A General Aspectsmentioning

confidence: 99%

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

et al. 2015

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“…Gemfibrozil glucuronide is often quoted as an example of a metabolite that causes significant DDI through inhibition of CYP2C8. This is certainly an exceptional case, and the presence of a mechanism-based inhibitor that is formed through further metabolism of a glucuronide is quite unique (Ogilvie et al, 2006;Jenkins et al, 2011). However, gemfibrozil is itself an inhibitor of CYP2C8 in vitro.…”

Section: Consideration Of Clinically Relevant Levels and Inhibition Pmentioning

confidence: 99%

A Perspective on the Contribution of Metabolites to Drug-Drug Interaction Potential: The Need to Consider Both Circulating Levels and Inhibition Potency

Tweedie

2012

Drug Metab Dispos

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The 2012 drug-drug interaction (DDI) guidance from the European Medicines Agency (EMA) and the draft DDI guidance from the Food and Drug Administration (FDA) have proposed that metabolites present at >25% of the parent area under the time-concentration curve (AUC) (EMA and FDA) and >10% of the total drug-related exposure (EMA) should be investigated in vitro for their DDI potential. This commentary attempts to rationalize the clinically relevant levels of metabolite(s) that contribute to DDI by considering not only the abundance but also inhibition potency, physicochemical properties, and structural alerts of the metabolite. A decision tree is proposed for levels of metabolites that could trigger in vitro DDI assessment. When the parent is an inhibitor of cytochrome P450s (P450s), clinical DDI studies will assess the in vivo DDI effect of the combination of parent and metabolite(s).When the parent is not a P450 inhibitor, it is important to assess the inhibition potential of abundant metabolites in vitro. The proposal is to apply a default cutoff value of metabolite level which is 100% of the parent AUC. It is important to note that exceptions can occur, and different metabolite levels may be considered depending on the physiochemical properties of metabolites (e.g., increased lipophilicity) and whether the metabolite contains structural alerts for DDI (e.g., mechanism-based inhibition). A key objective of this commentary is to stimulate discussions among the scientific community on this important topic, so that appropriate in vitro metabolism studies are conducted on metabolites, to ensure the safety of drugs in development balanced with the desire to avoid creating unnecessary studies that will add little to no value in ensuring patient safety.

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“…Contrasting with the in vitro findings, gemfibrozil-mediated pharmacokinetic interactions in vivo are mostly reported with CYP2C8 substrate drugs as exemplified by cerivastatin (5.6-fold increase in parent drug AUC) (Backman et al, 2002), montelukast (4.5-fold) (Karonen et al, 2010), atorvastatin (1.4-fold) (Whitfield et al, 2011), pioglitazone (3.4-fold) (Deng et al, 2005), loperamide (2.9-fold) (Niemi et al, 2006), rosiglitazone (2.3-fold) (Niemi et al, 2003), and repaniglide (7.0-fold) (Tornio et al, 2008). In large part, these interactions observed in vivo are not caused by gemfibrozil itself but by its 1-O-␤-glucuronide metabolite, which is a specific CYP2C8 mechanism-based inhibitor with a K i of 20 to 52 M and a k inact of 0.21 min Ϫ1 (Ogilvie et al, 2006;Jenkins et al, 2011). The glucuronide provides plasma peak concentrations close to those of the parent drug (Tornio et al, 2008), shows lower plasma protein binding (88.5 and 99.4%, respectively) (Shitara et al, 2004), and is reported to accumulate in the liver (Sabordo et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Effect of Gemfibrozil on the Metabolism of Brivaracetam In Vitro and in Human Subjects

Nicolas¹,

Chanteux²,

Rosa³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Brivaracetam (BRV) is a new high-affinity synaptic vesicle protein 2A ligand in phase III for epilepsy. Initial studies suggested that the hydroxylation of BRV into BRV-OH is supported by CYP2C8. Other metabolic routes include hydrolysis into a carboxylic acid derivative (BRV-AC), which could be further oxidized into a hydroxy acid derivative (BRV-OHAC). The aim of the present study was to investigate the effect of gemfibrozil (CYP2C9 inhibitor) and its 1-O-␤-glucuronide (CYP2C8 inhibitor) on BRV disposition both in vivo (healthy participants) and in vitro (human liver microsomes and hepatocytes). In a two-period randomized crossover study, 26 healthy male participants received a single oral dose of 150 mg of BRV alone or at steady state of gemfibrozil (600 mg b.i.d). Gemfibrozil did not modify plasma and urinary excreted BRV, BRV-OH, or BRV-AC. The only observed change was a modest decrease (approximately ؊40%) in plasma and urinary BRV-OHAC. In human hepatocytes and/or liver microsomes, gemfibrozil potently inhibited the hydroxylation of BRV-AC into BRV-OHAC (K i 12 M) while having a marginal effect on BRV-OH formation (K i >153 M). Gemfibrozil-1-O-␤-glucuronide had no relevant effect on either reaction (K i >200 M). In conclusion, gemfibrozil did not influence the pharmacokinetics of BRV and its hydroxylation into BRV-OH. Overall, in vitro and in vivo data suggest that CYP2C8 and CYP2C9 are not involved in BRV hydroxylation, whereas hydroxylation of BRV-AC to BRV-OHAC is likely to be mediated by CYP2C9.

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Studies to Further Investigate the Inhibition of Human Liver Microsomal CYP2C8 by the Acyl-β-Glucuronide of Gemfibrozil

Cited by 23 publications

References 20 publications

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

A Perspective on the Contribution of Metabolites to Drug-Drug Interaction Potential: The Need to Consider Both Circulating Levels and Inhibition Potency

Effect of Gemfibrozil on the Metabolism of Brivaracetam In Vitro and in Human Subjects

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