cerivastatin and Acute-Disease

We report on a patient who developed acute rhabdomyolysis after taking cerivastatin. A 74-year-old hypercholestrerolaemic woman taking cerivastatin (0.15 mg/day) for 22 days complained of general muscle weakness and muscle pain. Her serum creatinine phosphokinase level was 19,190 IU/L. Serum myoglobin was over 3000 ng/mL. Serum concentration of cerivastatin at 6 h after taking the last dose (0.15 mg) was 8062.5 ng/L, which was almost 5.7 times higher than that of normal persons. The serum concentration of cerivastatin showed that the half-life of cerivastatin in this patient was 22.4 h, compared with 2.4 h for normal controls. Cerivastatin is catabolized by cytochrome P450, 3A4 and 2C8 to M-1, and by 2C8 to M-23. The ratio of M-23 to M-1 in her serum was much lower than that of control persons (0.64 vs. 2.08). She had previously taken simvastatin which is metabolized by CYP3A4, without any sign and symptoms of rhabdomyolysis. These results suggest that the slowed clearance of cerivastatin in this patient might have been compounded by cytochrome P450, 2C8 dysfunction.

Topics: Acute Disease; Aged; Aryl Hydrocarbon Hydroxylases; Creatinine; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Administration Schedule; Female; Half-Life; Humans; Hypercholesterolemia; Metabolic Clearance Rate; Myoglobin; Myoglobinuria; Pyridines; Rhabdomyolysis; Simvastatin; Time Factors

Cerivastatine was administered as a reversible HMG-CoA reductase inhibitor (statine) to treat hypercholesterolemia until its withdrawal from the market following 52 reports of death due to drug-related rhabdomyolysis and acute renal failure. In most cases, cerivastatine was applied in combination with drugs which influenced the liver metabolism of cerivastatine via cytochromeoxidase P 450 isoenzymes. We report a well-documented case of acute rhabdomyolysis following cerivastatine monotherapy. The diagnosis was confirmed additionally by muscle biopsy.Finally,we give an overview of the current knowledge concerning therapy with HMG-CoA reductase inhibitors,1 year after the withdrawal of cerivastatine from the market.

Topics: Acute Disease; Anticholesteremic Agents; Aryl Hydrocarbon Hydroxylases; Biopsy; Coenzymes; Comorbidity; Creatine Kinase; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diagnosis, Differential; Drug Interactions; Electromyography; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Liver Cirrhosis, Alcoholic; Liver Function Tests; Middle Aged; Muscle, Skeletal; Neurologic Examination; Pancreatic Diseases; Pyridines; Rhabdomyolysis; Stomach Neoplasms; Ubiquinone

Statins are now widely prescribed and without doubt save many lives. However there are rare potentially serious side-effects, including acute renal failure. Patient education and physician vigilence are vital.

Topics: Acute Disease; Aged; Humans; Male; Muscle Weakness; Pyridines; Renal Insufficiency; Rhabdomyolysis

Topics: Acute Disease; Aged; Chemical and Drug Induced Liver Injury; Cholestasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Pyridines

The statin family of drugs inhibits 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway, and is used clinically as a safe and effective approach in the control of hypercholesterolemia. We have shown previously (Dimitroulakos, J., Nohynek, D., Backway, K. L., Hedley, D. W., Yeger, H., Freedman, M. H., Minden, M D., and Penn, L. Z. Increased sensitivity of acute myelogenous leukemias to lovastatin-induced apoptosis: a potential therapeutic approach. Blood, 93: 1308-1318, 1999) that lovastatin, a prototypic member of the statin family, can induce apoptosis of human acute myeloid leukemia (AML) cells in a sensitive and specific manner. In the present study, we evaluated the relative potency and mechanism of action of the newer synthetic statins, fluvastatin, atorvastatin, and cerivastatin, to trigger tumor-specific apoptosis. Cerivastatin is at least 10 times more potent than the other statins at inducing apoptosis in AML cell lines. Cerivastatin-induced apoptosis is reversible with the addition of the immediate product of the HMG-CoA reductase reaction, mevalonate, or with a distal product of the pathway, geranylgeranyl pyrophosphate. This suggests protein geranylgeranylation is an essential downstream component of the mevalonate pathway for cerivastatin similar to lovastatin-induced apoptosis. The enhanced potency of cerivastatin expands the number of AML patient samples as well as the types of malignancies, which respond to statin-induced apoptosis with acute sensitivity. Cells derived from acute lymphocytic leukemia are only weakly sensitive to lovastatin cytotoxicity but show robust response to cerivastatin. Importantly, cerivastatin is not cytotoxic to nontransformed human bone marrow progenitors. These results strongly support the further testing of cerivastatin as a novel anticancer therapeutic alone and in combination with other agents in vivo.

Topics: Acute Disease; Apoptosis; Atorvastatin; Cell Division; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Leukemia, Myeloid; Lovastatin; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyridines; Pyrroles; Sensitivity and Specificity; Tumor Cells, Cultured

Topics: Acute Disease; Aged; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis