Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus

Ichimaru, Naotsugu; Takahara, Shiro; Kokado, Yukito; Wang, Jing-Ding; Hatori, Motoaki; Kono, Hiroshi; Inoue, Takashi; Okuyama, Äkïhïko

doi:10.1016/s0021-9150(01)00438-5

Cited by 107 publications

(68 citation statements)

References 21 publications

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“…Several clinical studies have shown that immunosuppressants increase serum levels of cholesterol, TG and LDL-C, usually in a dose-dependent manner. 57,58 In the present study, KTR and CRF patients had increased TG levels compared with those of the control group. Lp (a) and apo B were also significantly higher in CRF cases compared to controls.…”

Section: Discussionsupporting

confidence: 46%

Adiponectin, leptin, nitric oxide, and C-reactive protein levels in kidney transplant recipients: comparison with the hemodialysis and chronic renal failure

2016

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Background: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with chronic kidney disease (CKD) including kidney transplant recipients (KTR). Secondary lipid metabolism disorders, endothelial dysfunction, and inflammation enhance the risk of CVD development in these patients. The aim of the present study was to investigate the lipid profile, adiponectin, leptin, nitric oxide (NO), and high sensitivity C-reactive protein (hs-CRP) levels in KTR and to compare these parameters with those of the patients with chronic renal failure (CRF), hemodialysis (HD) patients, and healthy controls. Methods: Serum adiponectin and leptin levels were measured by radioimmunoassay; hs-CRP was determined immunoturbidimetrically. Determination of NO was based on the Griess reaction. Results: Compared with the control group, serum NO and adiponectin levels were significantly higher in the KTR, CRF, and HD groups; hs-CRP levels were significantly higher in the KTR and HD groups; leptin levels were significantly higher in the KTR. In addition, serum NO level was significantly higher in the KTR compared to CRF cases. Adiponectin correlated positively with high density lipoprotein-cholesterol in the control and patient groups. A positive correlation was observed between hs-CRP and NO in the KTR and the patients with CRF. Serum adiponectin levels were inversely correlated with hs-CRP and leptin in the HD group. Conclusion: KTR suffer from inflammation and accompanying changes in levels of adipocytokines and NO which contribute to the increased risk of CVD in these patients.

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Section: Discussionsupporting

confidence: 46%

Adiponectin, leptin, nitric oxide, and C-reactive protein levels in kidney transplant recipients: comparison with the hemodialysis and chronic renal failure

2016

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“…This is illustrated by a study on the pharmacokinetics of simvastatin in transplant patients taking different calcineurin inhibitors. No alterations were seen in patients taking FK506, as opposed to those treated with CsA (25). However, apart from this small study, clinical and pharmacokinetic data on this topic with direct comparison between CsA, FK506 and Rapa are mostly lacking to date.…”

Section: Discussionmentioning

confidence: 71%

CYP3A4 and P-Glycoprotein Activity in Healthy Controls and Transplant Patients on Cyclosporin vs. Tacrolimus vs. Sirolimus

Lemahieu¹,

Maes²,

Verbeke³

et al. 2004

American Journal of Transplantation

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This study aimed to determine the impact of maintenance immunosuppressive therapy with cyclosporin A (CsA), tacrolimus (FK506) and sirolimus (Rapa) on the in vivo activity of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (PGP) in renal transplant patients. The activity of these four elimination pathways was measured by the recently validated intravenous (iv) and per oral (po) 14 C erythromycin breath and urine test. In addition, overall hepatic P450 activity was measured by the 13 C aminopyrin breath test. Three groups of stable renal transplant patients on maintenance therapy with corticosteroids (CS) and mycophenolate mofetil (MMF) plus either CsA or FK506 or Rapa were examined. A significant increase in intestinal CYP3A4 activity and a significant decrease in hepatic and intestinal PGP activity was seen in patients on CsA in comparison with those on FK506 or Rapa (p < 0.01). A similar analysis in six healthy volunteers at baseline and after intake of CsA, FK506 and Rapa confirmed the results seen in the patients. There was no difference in CYP3A4 and PGP activity in the patients taking either FK506 or Rapa and healthy controls. These data suggest that a different pattern of drug interactions might be expected in patients treated with CsA vs. FK506/Rapa.

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“…According to a recent study, clopidogrel does not cause a significant change in the disposition of simvastatin or its active acid form in humans (Itkonen et al, 2015). As simvastatin is among the most sensitive drugs to changes in CYP3A4 and OATP1B1 activity (Neuvonen et al, 1998;Backman et al, 2000;Ichimaru et al, 2001;Prueksaritanont et al, 2003;Pasanen et al, 2006;Niemi et al, 2011), clopidogrel is unlikely to have a clinically relevant effect on CYP3A4 or OATP1B1 activity (Itkonen et al, 2015). These findings indicate that inhibition of CYP2C8 by clopidogrel acyl-b-D-glucuronide is the main mechanism of the clopidogrel-cerivastatin and clopidogrel-repaglinide interactions (Floyd et al, 2012;Tornio et al, 2014;Itkonen et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone

Itkonen

Tornio

Neuvonen

et al. 2016

Drug Metabolism and Disposition

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The glucose-lowering drug pioglitazone undergoes hepatic CYP2C8-mediated biotransformation to its main metabolites. The antiplatelet drug clopidogrel is metabolized to clopidogrel acyl-b-D-glucuronide, which was recently found to be a strong time-dependent inhibitor of CYP2C8 in humans. Therefore, we studied the effect of clopidogrel on the pharmacokinetics of pioglitazone. In a randomized crossover study, 10 healthy volunteers ingested either 300 mg of clopidogrel on day 1, and 75 mg on days 2 and 3, or placebo. Pioglitazone 15 mg was administered 1 hour after placebo and clopidogrel on day 1. Plasma concentrations of pioglitazone, clopidogrel, and their main metabolites were measured up to 72 hours. Clopidogrel increased the area under the plasma concentration-time curve (AUC 0-' ) of pioglitazone 2.1-fold [P < 0.001, 90% confidence interval (CI) 1.8-2.6] and prolonged its half-life from 6.7 to 11 hours (P = 0.002). The peak concentration of pioglitazone was unaffected but the concentration at 24 hours was increased 4.5-fold (range 1.6-9.8; P < 0.001, 90% CI 3.17-6.45) by clopidogrel. The M-IV-to-pioglitazone AUC 0-' ratio was 49% (P < 0.001, 90% CI 0.40-0.59) of that during the control phase, indicating that clopidogrel inhibited the CYP2C8-mediated biotransformation of pioglitazone. Clopidogrel increases the exposure to pioglitazone by inhibiting its CYP2C8-mediated biotransformation. In consequence, use of clopidogrel may increase the risk of fluid retention and other concentration-related adverse effects of pioglitazone.

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Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus

Cited by 107 publications

References 21 publications

Adiponectin, leptin, nitric oxide, and C-reactive protein levels in kidney transplant recipients: comparison with the hemodialysis and chronic renal failure

Adiponectin, leptin, nitric oxide, and C-reactive protein levels in kidney transplant recipients: comparison with the hemodialysis and chronic renal failure

CYP3A4 and P-Glycoprotein Activity in Healthy Controls and Transplant Patients on Cyclosporin vs. Tacrolimus vs. Sirolimus

Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone

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