Simvastatin metabolism

A reduced response to simvastatin was noted after phenytoin was added for epilepsy the cholesterol level increased from 9.4 mmol/1 to 15.99 mmol/1. The level decreased again when phenytoin was discontinued. Phenytoin induces the CYP3A4 isoform which is involved in simvastatin metabolism. Some other examples of this type of interaction are shown in Table 5. 

Ubeaud G, Hagenbach J, Vandenschrieck S, Jung L, Koffel JC. In vitro inhibition of simvastatin metabolism in rat and human liver by naringenin. Life Sci 1999 65(13) 1403-1412. 

Le Goff-Klein N, Koffel JC, Jung L, Ubeaud G. In vitro inhibition of simvastatin metabolism, a HMG-CoA reductase inhibitor in human and rat liver by bergamottin, a component of grapefruit juice. Eur J Pharm Sci 2003 18(l) 31-35. 

Itraconazole probably inhibits simvastatin metabolism (SEDA 21, 459). 

An in vitro study using human liver microsomes also found that diltiazem moderately inhibits simvastatin metabolism. 

The clinical relevance of the verapamil interaction was demonstrated in a 63-year-old man, who developed rhabdomyolysis about 1 month after extended-release verapamil 240 mg daily was added to established treatment with simvastatin 40 mg daily and ciclosporin. Verapamil and simvastatin were discontinued and he recovered over the following 14 days. An in vitro study using human liver microsomes also found that verapamil moderately inhibits simvastatin metabolism. " ... 

Yeo KR, Yeo WW. Inhibitory effects of verq)amil and diltiazem on simvastatin metabolism inhuman liver microsomes. BrJClinPhanriacol (2001) 51,461—70. 

Carbamazepine is a known potent inducer of the cytochrome P450 isoenzyme CYP3A4 by which simvastatin is metabolised. Carbamazepine therefore increases simvastatin metabolism, leading to reduced levels. Lovastatin, and to a lesser extent, atorvastatin are also metabolised by... 

Bosentan is known to be a mild indueer of the cytochrome P450 isoenzyme CYP3A4, which is involved in the metabolism of simvastatin. In-duetion of simvastatin metabolism may have led to the redueed levels seen. See Lipid regulating drugs , (p.l086) for more information on the metabolism of all the statins. 

This potent inhibitor of cholesterol biosynthesis has been synthesized178 by one-pot esterification of the alcohol 210 with the acid chloride of 2,2-dimethylbutanoic[l-14C] acid, obtained by carbonation of the Grignard reagent prepared from 2-chloro-2-methylbutane (equation 74). Desilylation of 211 afforded [14C]simvastatin 209 in 29% radiochemical yield from 14C-labelled C02. This 14C-labelled drug was needed for elucidation of its metabolic fate in experimental animals. 

Drugs that may be affected by HMG-CoA reductase inhibitors include oral contraceptives, diclofenac, digoxin, glyburide, phenytoin, and warfarin. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4 they may interact with CYP3A4 inhibitors. 

E. Simvastatin. Itraconazole inhibits cytochrome P450 3A4. This cytochrome is responsible for metabolism of simvastatin. Therefore, itraconazole can increase serum level of simvastatin and increase its toxicity. 

Atorvastatin, simvastatin, rosuvastatin Inhibit HMG-CoA reductase Reduce cholesterol synthesis and up-regulate low-density lipoprotein (LDL) receptors on hepatocytes modest reduction in triglycerides Atherosclerotic vascular disease (primary and secondary prevention) t acute coronary syndromes Oral duration 12-24 h Toxicity Myopathy, hepatic dysfunction Interactions CYP-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors... 

Decreased metabolism of lovastatin, simvastatin, and, to a lesser extent, atorvastatin. 

The authors believed that either the two drugs had interacted by metabolism through the same hepatic enzyme, or that chlorzoxazone had caused cholestasis which then increased the blood concentration of simvastatin. 

A potential drug interaction between simvastatin and danazol, causing rhabdomyolysis and acute renal insufficiency, has been reported (43). Rhabdomyolysis can occur with all statins when they are used alone and particularly when they are combined with other drugs that are themselves myotoxic or that increase the concentration of the statin. Statins are particularly susceptible to the latter effect because of their metabolism by the CYP450 system and their low oral systemic availability. 

Erythromycin interacts with simvastatin, probably by inhibiting its metabolism by CYP3A4. In a randomized, double-blind crossover study in 12 healthy volunteers, erythromycin significantly increased mean peak serum concentration and AUC for both unchanged simvastatin and its active metabolite simvastatin acid. However, there was extensive interindividual variability in the extent of this interaction (50). 

Rifampicin greatly reduced the plasma concentrations of simvastatin and simvastatin acid in 10 healthy volunteers in a randomized, crossover study (57). Because the half-life of simvastatin was not affected by rifampicin, induction of CYP3A4-mediated first-pass metabolism of simvastatin in the intestine and liver probably explains this interaction. 

Md.K. Pasha, S. Muzeeb, S.J.S. Basha, D. Shashikumar, R. Mullangi, N.R. Srinivas, Analysis of five HMG-CoA reductase inhibitors—atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin pharmacological, pharmacokinetic and analytical overview and development of a new method for use in pharmaceutical formulations analysis and in vitro metabolism studies, Biomed. Chromatogr. 20 (2006) 282-293. 

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