Simvastatin CYP3A4 inhibition

CYP3A4 Inhibition Amiodarone, clarithromycin, erythromycin, cimetidine, cyclosporine, fluoxetine fluvoxamine, itraconazole, ketoconazole, nefazodone, verapamil, diltiazem HIV antivirals delaviridine, indanavire, nelfmavire, ritonavire, sequinavire Atorvastatin Lovastatin Simvastatin ... 

Simvastatin Rhabdomyolysis after combined therapy with simvastatin 80 mg/day and clarithromycin has been recently reported in two women they recovered rapidly, after simvastatin withdrawal [13T, 132 ]. The interacting mechanism was probably inhibition of CYP3A4 inhibition of P glycoprotein transport of simvastatin may also have contributed. 

The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, whereas that of fluvastatin and rosuvastatin is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include the macrolide antibiotics, cyclosporine, ketoconazole and its congeners, HIVprotease inhibitors, tacrolimus, nefazodone, fibrates, and others (see Chapter 4). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy. 

Tipranavir both inhibits and induces the CYP3A4 system. When used in combination with ritonavir, its net effect is inhibition. Tipranavir also induces P-glycoprotein transporter and thus may alter the disposition of many other drugs (Table 49-4). Concurrent administration of tipranavir with fosamprenavir or saquinavir should be avoided owing to decreased blood levels of the latter drugs. Tipranavir/ritonavir may also decrease serum levels of valproic acid and omeprazole. Levels of lovastatin, simvastatin, atorvastatin, and rosuvastatin may be increased, increasing the risk for rhabdomyolysis and myopathy. 

Simvastatin is an HMG Co-A reductase inhibitor. Its most serious adverse effect is rhabdomyolysis, which is enhanced by other drugs that inhibit CYP3A4 (1). 

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). 

Grapefruit juice has also been shown to inhibit CYP3A4 and P-gp in the small intestine, and hence, can elevate the oral bioavailability of lipophilic drugs [98,99]. Concomitant intake of grapefruit juice with the lipophilic cholesterol-lowering medication simvastatin caused a 16-fold increase in the AUC of simvastatin [100]. The oral bioavailability of the lipophilic HIV protease inhibitor saquinavir was doubled following concomitant administration with grapefruit juice [101]. 

Nefazodone can cause myositis and rhabdomyolysis in patients taking pravastatin and simvastatin (25). The postulated mechanism involves inhibition of CYP3A4, leading to reduced clearance of the HMG-CoA reductase inhibitors and muscle toxicity. 

VASODILATOR ANTIHYPERTENSIVES LIPID-LOWERING DRUGS Bosentan lowers simvastatin levels Uncertain bosentan moderately inhibits CYP3A4 Monitor lipid profile closely look for poor response to simvastatin... 

CALCIUM CHANNEL BLOCKERS STATINS t plasma levels of atorvastatin, lovastatin and simvastatin case reports of myopathy when atorvastatin and simvastatin are co-administered with diltiazem or verapamil Uncertain, but postulated to be due to inhibition of CYP3A4-mediated metabolism of statins in the intestinal wall. Also, diltiazem and verapamil inhibit intestinal P-gp, which may t the bioavailability of statins Watch for side-effects of statins. It has been suggested that the dose of simvastatin should not exceed 20 mg when given with verapamil, and 40 mg when given with diltiazem... 

ATORVASTATIN, SIMVASTATIN MACROLIDES Macrolides may t levels of atorvastatin and simvastatin the risk of myopathy t over 10-fold when eiythromycin is co-administered with a statin Macrolides inhibit CYP3A4-mediated metabolism of atorvastatin and simvastatin. Also, erythromycin and clarithromycin inhibit intestinal P-gp, which may t the bioavailability of statins Avoid co-administration of macrolides with atorvastatin or simvastatin (temporarily stop the statin if the patient needs macrolide therapy). Manufacturers also recommend that patients be warned to look for the early signs of rhabdomyolysis when other statins are co-ingested with macrolides... 

ATORVASTATIN, SIMVASTATIN IMATINIB Imatinib may t atorvastatin and simvastatin levels Imatinib inhibits CYP3A4-mediated metabolism of simvastatin Monitor LFTs, U Es and CK closely... 

STATINS ANTIPLATELET AGENTS -CLOPIDOGREL Atorvastatin and possibly simvastatin 1 the antiplatelet effect of dopidogrel in a dose-dependent manner Atorvastatin and simvastatin inhibit CYP3A4-mediated activation of dopidogrel Use these statins at the lowest possible dose otherwise consider using an alternative statin... 

LOVASTATIN, SIMVASTATIN PROTEASE INHIBITORS t risk of adverse effects Inhibition of CYP3A4-mediated metabolism of simvastatin Avoid co-administration... 

STATINS GRAPEFRUIT JUICE t levels with simvastatin slight rise with atorvastatin. t risk of adverse effects such as myopathy Constituent of grapefruit juice inhibits CYP3A4-mediated metabolism of simvastatin Patients taking simvastatin and atorvastatin should avoid grapefruit juice... 

A 52-year-old man developed rhabdomyolysis while taking simvastatin, digoxin, ciclosporin, and verapamil (298). The authors proposed that this had been due in part to inhibition of the biliary secretion of simvastatin by digoxin however, it is likely that the major mechanism of the interaction was inhibition of CYP3A4 by ciclosporin. 

Mibefradil inhibits CYP3A4 (2). Other drugs that are metabolized by this pathway accumulate as a result. Drugs that were commonly affected included amiodarone, astemizole, ciclosporin, cisapride, erythromycin, imi-pramine, lovastatin, propafenone, quinidine, simvastatin (9), tacrohmus (10), tamoxifen, terfenadine, thioridazine, and drugs that impair sinoatrial node function (for example beta-blockers) (6). 

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