Gemfibrozil Inhibits CYP2C8-Mediated Cerivastatin Metabolism in Human Liver Microsomes

Wang, Junsheng; Neuvonen, Mikko; Xia, Wenle; Backman, Janne T.; Neuvonen, Pertti J.

doi:10.1124/dmd.30.12.1352

Cited by 167 publications

(168 citation statements)

References 18 publications

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“…Fluvoxamine 0.06-0.23 (Schulz et al, 2012) 0.2-0.7 0.2 (Brosen et al, 1993) Amiodarone 0.5-2.5 (Schulz et al, 2012) 0.7-3.9 86 (Kobayashi et al, 1998) Efavirenz > 1 (Schulz et al, 2012) > 3.2 6 (Xu and Desta, 2013) Gemfibrozil 25 (Schulz et al, 2012) 91 (Wang et al, 2002) Fluconazole 1-5 (Schulz et al, 2012) 4.9-16.3 30.3 (Niwa et al, 2005) Chloramphenicol 5-10 (Schulz et al, 2012) 15.5-31 32 (Park et al, 2003) Fluoxetine 0.12-0.5 (Schulz et al, 2012) 0.4-1.6…”

Section: Known Inhibitorsmentioning

confidence: 99%

“…A tryptamine concentration of 100 µM was chosen because at that concentrations, no or only slight inhibition could be considered as clinically irrelevant. Clinically relevant inhibitors showed IC50 values of about 100 µM (Bertelsen et al, 2003;Brosen et al, 1993;Burt et al, 2010;Ewald and Maurer, 2008;Kobayashi et al, 1998;Niwa et al, 2005;Park et al, 2003;von Moltke et al, 1998;Wang et al, 2002;Xu and Desta, 2013). Therefore, the IC50 values were only determined for TDNPS that showed inhibition of more than 50%.…”

Section: Prescreening and Determination Of Ic50 Valuesmentioning

confidence: 99%

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Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class

et al. 2016

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R., Maurer, Hans H., Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class.Toxicology Letters http://dx.doi.org/10.1016/j.toxlet. 2015.11.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.  IC50 values were comparable to that of clinically relevant inhibitors. Members of the DALT family were strong inhibitors of CYP1A2 and CYP2D6 activity. 5-MeO-DALT showed in vivo inhibition against CYP1A2 activity. ABSTRACTNew psychoactive substances (NPS) are not tested for their cytochrome P450 (CYP) inhibition potential before consumption. Therefore, this potential was explored for tryptamine-derived NPS (TDNPS) including alpha-methyl tryptamines (AMTs), dimethyl tryptamines (DMTs), diallyl tryptamines (DALTs), and diisopropyl tryptamines (DiPTs) using test substrates preferred by the Food and Drug Administration in a cocktail assay. All tested TDNPS with the exception of DMT inhibited CYP2D6 activity with IC50 values below 100 µM. DALTs inhibited CYP2D6 activity similar to paroxetine and quinidine and CYP1A2 activity comparable to fluvoxamine. 5-Methoxy-N,N-diallyltryptamine reduced in vivo the caffeine metabolism in rats consistent with in vitro results. Five of the AMTs also inhibited CYP1A2 activity comparable to amiodarone. AMT and 6-F-AMT inhibited CYP2A6 activity in the range of the test inhibitor tranylcypromine. CYP2B6 activity was inhibited by 19 tryptamines, but weakly compared to efavirenz. CYP2C8 activity was inhibited by five of the tested TDNPS and three showed values comparable to trimethoprim and gemfibrozil. Six tryptamines inhibited CYP2C9 and seven CYP2C19 activities comparable to fluconazole and chloramphenicol, respectively. Nineteen compounds showed inhibition of CYP2E1 and 18 of CYP3A activity, respectively. These results showed that the CYP inhibition by TDNPS might be clinically relevant, but clinical studies are needed to explore this further.

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Section: Known Inhibitorsmentioning

confidence: 99%

Section: Prescreening and Determination Of Ic50 Valuesmentioning

confidence: 99%

Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class

et al. 2016

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“…Repaglinide is completely metabolised, and cytochromes P-450 (CYP) 2C8 and 3A4 participate in its biotransformation in vitro [2]. Fibrates like gemfibrozil are widely used in the treatment of diabetic dyslipidaemia, and gemfibrozil was recently found to inhibit CYP2C8 [3,4]. Several commonly used drugs, such as the antimycotic itraconazole, are inhibitors of CYP3A4 [5].…”

mentioning

confidence: 99%

Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide

et al. 2003

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Aims/hypothesis. Our aim was to investigate possible interactions of gemfibrozil, itraconazole, and their combination with repaglinide. Methods. In a randomised crossover study, 12 healthy volunteers received twice daily for 3 days either 600 mg gemfibrozil, 100 mg itraconazole (first dose 200 mg), both gemfibrozil and itraconazole, or placebo. On day 3 they ingested a 0.25 mg dose of repaglinide. Plasma drug and blood glucose concentrations were followed for 7 h and serum insulin and C-peptide concentrations for 3 h postdose. Results. Gemfibrozil raised the area under the plasma concentration-time curve (AUC) of repaglinide 8.1-fold (range 5.5-to 15.0-fold; p<0.001) and prolonged its half-life (t 1/2 ) from 1.3 to 3.7 h (p<0.001). Although itraconazole alone raised repaglinide AUC only 1.4-fold (1.1-to 1.9-fold; p<0.001), the gemfibrozil-itraconazole combination raised it 19.4-fold (12.9-to 24.7-fold) and prolonged the t 1/2 of repaglinide to 6.1 h (p<0.001). Plasma repaglinide concentration at 7 h was increased 28.6-fold by gemfibrozil and 70.4-fold by the gemfibrozil-itraconazole combination (p<0.001). Gemfibrozil alone and in combination with itraconazole considerably enhanced and prolonged the blood glucose-lowering effect of repaglinide; i.e., repaglinide became a long-acting and stronger antidiabetic. Conclusion/interpretation. Clinicians should be aware of this previously unrecognised and potentially hazardous interaction between gemfibrozil and repaglinide. Concomitant use of gemfibrozil and repaglinide is best avoided. If the combination is considered necessary, repaglinide dosage should be greatly reduced and blood glucose concentrations carefully monitored. [Diabetologia (2003) 46:347-351] Keywords CYP2C8, CYP3A4, drug interaction, gemfibrozil, hypoglycaemia, itraconazole, repaglinide. Corresponding author: P. J. Neuvonen, Department of Clinical Pharmacology, Helsinki University Central Hospital, P.O. Box 340, 00029, HUS, Finland E-mail: pertti.neuvonen@hus.fi Abbreviations: AUC, area under the concentration-time curve from time zero to infinity; AUC 0-7 , area under the concentration-time curve from time zero to 7 h; AUC 0-8 , area under the concentration-time curve from time zero to 8 h; C 7 , concentration at 7 h; C max , peak concentration; CYP, cytochrome P450; t max , time to peak concentration; t 1/2 , elimination halflife.

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“…CYP2C8 is a pivotal enzyme in the catalyzing pathway of cerivastatin that is also highlighted by the recent report showing that the drug gemfibrozil, when interacting with cerivastatin, inhibits CYP2C8 activity in human liver microsome (Wang et al 2002). The patient most likely lacks the enzyme activity of CYP2C8 due to the homozygous mutation of 475delA that loses 64% of the protein structure.…”

Section: Resultsmentioning

confidence: 97%

“…However, despite the dual metabolizing pathways, cerivastatin caused rhabdomyolysis more frequently than other statins, especially when cerivastatin was given together with other drugs such as gemfibrozil (Farmer 2001;Staffa et al 2002). In vitro experiment with human liver microsome demonstrated that gemfibrozil inhibited CYP2C8 activity leading to a decreased level of M-23 in the cerivastatin-metabolizing pathway, which at least partially explains the interaction between gemfibrozil and cerivastatin (Wang et al 2002). Because of the adverse effects in the muscles causing rhabdomyolysis, cerivastatin was withdrawn from the market in August 2001.…”

Section: Introductionmentioning

confidence: 99%

A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin

et al. 2004

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A hypercholesterolemic patient medicated with cerivastatin for 22 days resulted in acute rhabdomyolysis. CYP2C8 and CYP3A4 are the major enzymes responsible for the metabolism of cerivastatin, and a transporter, OATP2, contributes to uptake of cerivastatin to the liver. In this study, the patient's DNA was sequenced in order to identify a variant that would lead to the adverse effect of cerivastatin. Three nucleotide variants, 475delA, G874C, and T1551C, were found in the exons of CYP2C8. The patient was homozygous for 475delA variant that leads to frameshift and premature termination. Accordingly, the patient is most likely lacking the enzyme activity. The patient's children were both heterozygous for the mutation. The patient had three nucleotide variants in exon 4 (A388G) and exon 5 (C571T and C597T) of OATP2 that were all heterozygous. No nucleotide variation in the exons of CYP3A4 was identified. To our knowledge, this is the first report showing that the adverse effect of cerivastatin might be caused by the genetic variant of CYP2C8.

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Gemfibrozil Inhibits CYP2C8-Mediated Cerivastatin Metabolism in Human Liver Microsomes

Cited by 167 publications

References 18 publications

Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class

Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class

Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide

A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin

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