Atorvastatin-induced acute elevation of hepatic enzymes and the absence of cross-toxicity of pravastatin

Liu, Y.; Cheng, Zhiyuan; Ding, Lei; Fang, Fanfu; Cheng, Ken-Sheng; Fang, Qin; Shi, Guo-Bing

doi:10.5414/cpp48798

Cited by 25 publications

(19 citation statements)

References 20 publications

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“…Moreover, the implication of such drug interaction in the liver may seem inconsequential because the frequency of reported hepatotoxicity with atorvastatin is rare considering its prevalent use. However, this may be attributed to the fact that atorvastatin is already contraindicated with strong CYP3A4 inhibitors (LIPITOR, 2012); and indeed, hepatotoxicity was observed when atorvastatin was administered with CYP3A4 inhibitor diltiazam (Lewin et al, 2002;Liu et al, 2010). In addition, data presented in this study provide the first set of evidence on the potential risk of hepatotoxicity when blocking metabolism, despite only small changes in the plasma compartment.…”

Section: Discussionmentioning

confidence: 67%

Differential Effects of Rifampin and Ketoconazole on the Blood and Liver Concentration of Atorvastatin in Wild-Type and Cyp3a and Oatp1a/b Knockout Mice

Chang¹,

Ly²,

Plise³

et al. 2014

Drug Metab Dispos

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Atorvastatin is eliminated by CYP3A4 which follows carrier-mediated uptake into hepatocytes by OATP1B1, OATP1B3, and OATP2B1. Multiple clinical studies demonstrated that OATP inhibition by rifampin had a greater impact on atorvastatin systemic concentration than itraconazole-mediated CYP3A4 inhibition. If it is assumed that the blood and hepatocyte compartments are differentiated by the concentration gradient that is established by OATPs, and if the rate of uptake into the hepatocyte is rate-determining to the elimination of atorvastatin from the body, then it is hypothesized that blood concentrations may not necessarily reflect liver concentrations. In wild-type mice, rifampin had a greater effect on systemic exposure of atorvastatin than ketoconazole, as the blood area under the blood concentration-time curve increased 7-and 2-fold, respectively. In contrast, liver concentrations were affected more by ketoconazole than by rifampin, as liver levels increased 21-and 4-fold, respectively. Similarly, in Cyp3a knockout animals, 39-fold increases in liver concentrations were observed despite insignificant changes in the blood area under the blood concentration-time curve. Interestingly, blood and liver levels in Oatp1a/b knockout animals were similar to wild types, suggesting that Oatp1a/b knockout may be necessary but not sufficient to completely describe atorvastatin uptake in mice. Data presented in this work indicate that there is a substantial drug interaction when blocking atorvastatin metabolism, but the effects of this interaction are predominantly manifested in the liver and may not be captured when monitoring changes in the systemic circulation. Consequently, there may be a disconnect when trying to relate blood exposure to instances of hepatotoxicity because a pharmacokinetictoxicity relationship may not be obvious from blood concentrations.

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Section: Discussionmentioning

confidence: 67%

Differential Effects of Rifampin and Ketoconazole on the Blood and Liver Concentration of Atorvastatin in Wild-Type and Cyp3a and Oatp1a/b Knockout Mice

Chang¹,

Ly²,

Plise³

et al. 2014

Drug Metab Dispos

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“…The most frequent adverse effects are mild (such as gastrointestinal upset or discolored urine). The major clinical trouble associated with statin therapy is the hepatotoxicity characterized by an increase of hepatic aminotransferases, hepatocellular and cholestatic injury, autoimmune-type reactions, and fulminant liver failure (Liu et al, 2010). In addition, myotoxicity (myalgia, myopathy) occurs in approximately 10% of statin-treated patients, and it may progress to rhabdomyolysis, commonly characterized by massive muscle necrosis, myoglobinuria, and acute renal failure (Williams and Feely, 2002).…”

Section: Statins and Cancer: Pros And Consmentioning

confidence: 99%

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Gazzerro

Proto²,

Gangemi³

et al. 2011

Pharmacol Rev

388

361

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“…Liver enzymes reflect hepatocyte integrity or cholestasis, the later increases ALP level [15] whereas ALT is elevated whenever there is hepatocyte injury [16]. Liver disease can be divided into different categories according to ALT and ALP level and the ratio between them [17]. Both STZ and DM can cause hepatic histopathological changes.…”

Section: Effect Of Drugs and Diabetes On The Livermentioning

confidence: 99%

Histopathological Alteration in STZ-Nicotinamide Diabetic Rats, a Complication of Diabetes or a Toxicity of STZ?

Mh¹,

Imt²,

A³

et al. 2018

Int J Diabetes Clin Res

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Background: Type 2 diabetes mellitus (T2DM) previously known as non-insulin dependent diabetes mellitus is the most common type of diabetes mellitus. The rapid increasing prevalence, high morbidity and mortality of the disease must be encountered by an increase in scientific research. Animal models are very important in the preclinical studies to validate the use of new drugs. Streptozotocin-nicotinamide (STZ-NA) is used to induce T2DM in animals. Aim: The aim of this study was to assess STZ-NA as a model of T2DM and to investigate the causative factors that lead to hepatic histopathological changes. Methodology: Twenty-five male Wistar rats were divided into four groups. One normal non-diabetic control group (NNC) (n = 6), two diabetic groups subdivided into non-treated diabetic group (NTD) (n = 6) and metformin treated diabetic group (MTD) (n = 7) and the fourth group was composed of rats failed to develop diabetes [failed induction group (FIG)] (n = 6). Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg-bw) 15 min after intraperitoneal administration of nicotinamide (120 mg/kgbw). Induction of diabetes was confirmed after 72 hours by fasting blood glucose (FBG) ≥ 250 mg/dl. 8 weeks after induction, oral glucose tolerance test was performed; blood samples were taken for analysis of lipid profile, urea, creatinine and hepatic enzymes; samples from the liver were prepared for histopathological study and samples from the skeletal muscles were taken for determination of insulin receptor content by Elisa. Results: Metformin improved glucose intolerance. Serum high density lipoprotein cholesterol (HDL-C) was significantly reduced in the NTD group compared with the NNC group (P value 0.006) whereas no significant difference in low density lipoprotein cholesterol and triglycerides detected. Skeletal muscle insulin receptor was reduced in both diabetic groups yet, reduction was significant in MTD group compared with NTD group [P values were (0.01) and (0.06) in the MTD and NTD respectively]. Hepatic enzymes, urea and creatinine were within normal range. Histopathological study revealed hepatic histopathological alterations which were more obvious in NTD compared with MTD and FIG. Conclusion: Our study showed that STZ-NA is a good model for T2DM regarding hyperglycemia, response to metformin, dyslipidemia and the histopathological changes. In addition, it emphasized that hepatic hydropic degeneration of the hepatocytes was a consequence of diabetes rather than STZ.

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Atorvastatin-induced acute elevation of hepatic enzymes and the absence of cross-toxicity of pravastatin

Cited by 25 publications

References 20 publications

Differential Effects of Rifampin and Ketoconazole on the Blood and Liver Concentration of Atorvastatin in Wild-Type and Cyp3a and Oatp1a/b Knockout Mice

Differential Effects of Rifampin and Ketoconazole on the Blood and Liver Concentration of Atorvastatin in Wild-Type and Cyp3a and Oatp1a/b Knockout Mice

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Histopathological Alteration in STZ-Nicotinamide Diabetic Rats, a Complication of Diabetes or a Toxicity of STZ?

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