Grapefruit juice—simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors*

Lilja, Jari J.; Kivistö, Kari T.; Neuvonen, Pertti J.

doi:10.1016/s0009-9236(98)90130-8

Cited by 263 publications

(168 citation statements)

References 15 publications

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“…Simvastatin also suppressed adipocyte differentiation, but only at 1,000 ng/ml, which is 2-4 logarithmic orders higher than its plasma concentration in patients receiving this drug [29,30]. Pravastatin had little effect on adipocyte differentiation.…”

Section: Discussionmentioning

confidence: 86%

Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control

et al. 2006

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Aims/hypothesis: Hyperlipidaemia often occurs in patients with type 2 diabetes mellitus. Though HMGCoA reductase inhibitors (statins) are widely used for controlling hypercholesterolemia, atorvastatin has also been reported to have an adverse effect on glucose metabolism. Based on these findings, the aim of this study was to investigate the effects of statins on adipocytes, which play pivotal roles in glucose metabolism. Methods: In 3T3-L1 cells, effects of statins on adipocyte maturation were determined morphologically. Protein and mRNA levels of SLC2A4 and adipocyte marker proteins were determined by immunoblotting and RT-PCR, respectively. Type 2 diabetic NSY mice were treated with atorvastatin for 15 weeks, followed by glucose and insulin tolerance tests and examination of SLC2A4 expression in white adipose tissue (WAT). Seventy-eight Japanese subjects with type 2 diabetes and hypercholesterolaemia were treated with atorvastatin (10 mg/day), and its effects on lipid and glycaemic profiles were measured 12 weeks after treatment initiation.Results: Treatment with atorvastatin inhibited adipocyte maturation, SLC2A4 and C/EBPα expressions and insulin action in 3T3-L1 cells.Atorvastatin also attenuated SLC2A4 and C/EBPα expressions in differentiated 3T3-L1 adipocytes. These effects were reversed by L-mevalonate or geranylgeranyl pyrophosphate. In NSY mice, atorvastatin accelerated glucose intolerance as a result of insulin resistance and decreased SLC2A4 expression in WAT. In addition to improving hyperlipidaemia, atorvastatin treatment significantly increased HbA 1c but not fasting glucose levels in diabetic patients, and this effect was greater in the nonobese subgroup. Conclusions/interpretation: These results demonstrate that atorvastatin attenuates adipocyte maturation and SLC2A4 expression by inhibiting isoprenoid biosynthesis, and impairs glucose tolerance. These actions of atorvastatin could potentially affect the control of type 2 diabetes.

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Section: Discussionmentioning

confidence: 86%

Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control

et al. 2006

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“…The use of concomitant medications that could potentially alter the integrity of the PK analysis (e.g., altered absorption, distribution) was forbidden. The patients were asked to refrain from strenuous physical exercise (e.g., weight training, aerobics, football) for 7 days before dosing until after the study completion evaluation, from alcohol for 72 h before dosing until after the study completion evaluation and from intake of xanthine (e.g., caffeine) or grapefruit (known as a CYP3A4 inhibitor (Schmiedlin-Ren et al, 1997;Lilja et al, 1998;Kane and Lipsky, 2000))-containing food or beverages 48 h before dosing and during the whole study.…”

Section: Patient Populationmentioning

confidence: 99%

Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome P450 3A4 substrate, in patients with chronic myeloid leukaemia

et al. 2003

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The inhibition by imatinib of the cytochrome P450 3A4 isoenzyme may reduce the CYP3A4-mediated metabolic clearance of clinically important coadministered drugs. The main purpose of this study was to evaluate the effect of the coadministration of imatinib on the pharmacokinetics of simvastatin, a probe CYP3A4 substrate. In total, 20 patients with chronic myeloid leukaemia received an oral dose of 40 mg of simvastatin on study day 1. On study days 2 -7, each patient received 400 mg of imatinib once daily orally and on study day 8, 400 mg imatinib together with 40 mg of simvastatin was given. Blood levels of simvastatin were measured predose and for 24 h postdose on study days 1 and 8. Two additional blood samples were taken for imatinib pharmacokinetic (PK) assessment on day 8 before, and 24 h after, imatinib administration. Imatinib increased the mean maximum concentration (C max ) value of simvastatin two-fold and the area under concentration -time curve (AUC (0 -inf) ) value 3.5-fold (Po0.001) compared with simvastatin alone. There was a statistically significant decrease in total-body clearance of drug from the plasma (CL/F) with a mean reduction of 70% for simvastatin (Po0.001): the mean half-life of simvastatin was prolonged from 1.4 -2.7 h when given together with imatinib. No changes in imatinib PK parameters were found when given concomitantly with simvastatin. In conclusion, the coadministration of imatinib at steady state with 40 mg simvastatin increases the exposure (C max and AUCs) of simvastatin significantly (Po0.001) by two-three-fold. Caution is therefore required when administering imatinib with CYP3A4 substrates with a narrow therapeutic window. The coadministration of simvastatin with imatinib (400 mg) was well tolerated and no major safety findings were reported in this study.

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“…Grapefruit juice has been shown to increase the serum concentrations of simvastatin (65) and lovastatin (52), two HMG-CoA reductase inhibitors commonly used for the treatment of hypercholesterolemia. This is thought to occur by inhibition of CYP3A4-mediated firstpass metabolism of the HMG-CoA reductase inhibitors in the small intestine, as discussed earlier.…”

Section: Naringenin Drug Interactionsmentioning

confidence: 99%

Antiatherogenic Properties of Naringenin, a Citrus Flavonoid

Wilcox

Borradaile

Huff

1999

Cardiovascular Drug Reviews

128

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Grapefruit juice—simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors*

Cited by 263 publications

References 15 publications

Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control

Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control

Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome P450 3A4 substrate, in patients with chronic myeloid leukaemia

Antiatherogenic Properties of Naringenin, a Citrus Flavonoid

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