Lovastatin Erythromycin

Lovastatin, simvastatin Ketoconazole, erythromycin, etc. CYP3A4 Rhabdomyolysis... 

In some cases enzymes can increase the rate of reaction by up to lO times. Carnell and Roberts (1997) have briefly discussed the scope of biotransformations that are used to make pharmaceuticals like penicillins, cephalosporines, erythromycin, lovastatin, cyclosporin, etc., and for food additives like citric acid, L-glutamate, and L-lysine. A very successful transformation by Zeneca has been that of benzene reduction, with Pseudomonase Putida, to dihydrocatechol and catechol the dihydro derivative is used to produce (+/-) pinitol. Fluorobenzene has been converted to fluorodihydrocatechol, an intermediate for pharmaceuticals. The highly stereo selective Bayer-Villeger reaction has been carried out with genetically engineered S-cerevisvae. Hydrolases have allowed enantioselective, and in some cases regioselective, hydrolysis of racemic esters. 

Lovastatin (Mevacor/ Altocor) [Antilipemic/HMG-CoA Reductase Inhibitor] Uses Hypercholesterolemia Action HMG-CoA reductase inhibitor Dose 20 mg/d PO w/ PM meal may T at 4-wk intervals to 80 mg/d max or 60 mg ER tab take w/ meals Caution [X, -] Avoid w/ grapefruit juice, gemfibrozil. Contra Active liver Dz Disp Tabs SE HA GI intolerance common promptly report any unexplained muscle pain, tenderness, or weakness (myopathy) Interactions T Effects W/ grapefruit juice T risk of severe myopathy W/ azole antifungals, cyclosporine, erythromycin, gemfibrozil, HMG-CoA inhibitors, niacin T effects OF warfarin >1 effects W/ isradipine, pectin EMS t Risk of photosensitivity Rxns T effects of warfarin concurrent EtOH use t risk of liver tox diltiazem and verapamil can T risk of lovastatin tox OD Unlikely to cause life-threatening Sxs... 

The risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Lovastatin is metabolized by the CYP isoform 3A4. Certain drugs, that share this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include cyclosporine, itraconazole, ketoconazole and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (greater than 1 quart daily)... 

Spach DH, Bauwens JE, Clark CD, Burke WG. Rhabdomyolysis associated with lovastatin and erythromycin use. West J Med 1991 154(2) 213-5. 

Rhabdomyolysis due to a short course of erythromycin in a 73-year-old man who had taken lovastatin for 7 years was accompanied by signs of multiple organ toxicity so severe as to mimic sepsis (13). 

Rhabdomyolysis with or without renal impairment has been reported in patients taking both erythromycin and lovastatin (14). The exact mechanism is unknown, but lovastatin is extensively metabolized by CYP3A4 and its metabolism may therefore be inhibited by erythromycin. The manufacturers have advised that careful monitoring is required when these two drugs are given together. 

Rhabdomyolysis, acute renal insufficiency, pancreatitis, ileus, livedo reticularis, and raised transaminase activities developed in a patient who had taken lovastatin for 7 years and took erythromycin before a dental procedure. 

In a review of the literature, three other reported instances of erythromycin and lovastatin interaction presenting with rhabdomyolysis, raised transaminase activities, and acute renal insufficiency were identified (19). 

Wong PW, Dillard TA, Kroenke K. Multiple organ toxicity from addition of erythromycin to long-term lovastatin therapy. South Med J 1998 91(2) 202-5. 

A4 Acetaminophen, alfentanil, amiodarone, astemizole, cocaine, cortisol, cyclosporine, dapsone, diazepam, dihydroergotamine, dihydropyridines, diltiazem, ethinyl estradiol, gestodene, indinavir, lidocaine, lovastatin, macrolides, methadone, miconazole, midazolam, mifepristone (RU 486), paclitaxel, progesterone, quinidine, rapamycin, ritonavir, saquinavir, spironolactone, sulfamethoxazole, sufentanil, tacrolimus, tamoxifen, terfenadine, testosterone, tetrahydro-cannabinol, triazolam, troleandomycin, verapamil Barbiturates, carbamazepine, macrolides, glucocorticoids, pioglitazone, phenytoin, rifampin Erythromycin, 613-hydroxy cortisol... 

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

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). 

Benzodiazepines alprazolam, clonazepam, diazepam, midazolam, triazolam, zolpidem Calcium channel blockers diltiazem, nifedipine, nimodipine, verapamil Steroids androgens, estrogens, cortisol Others erythromycin, terfenadine, cyclosporine, dapsone, ketoconazole, lovastatin, lidocaine, alfentanil, amiodarone, astemizole, codeine, sildenafil... 

Clinically important, potentially hazardous interactions with amiloride, aminoglycosides, amphotericin B, ampicillin, anisindione, anticoagulants, armodafinil, atorvastatin, azathioprine, azithromycin, bacampicillin, basiliximab, bezafibrate, bosentan, bupropion, carbenicillin, caspofungin, cholestyramine, clarithromycin, cloxacillin, co-trimoxazole, corticosteroids, cyclophosphamide, daclizumab, danazol, dicloxacillin, dicumarol, digoxin, diltiazem, disulfiram, echinacea, erythromycin, ethotoin, etoposide, ezetimibe, flunisolide, fluoxymesterone, fluvastatin, foscarnet, fosphenytoin, gemfibrozil, hemophilus B vaccine, HMG-CoA reductase inhibitors, imatinib, imipenem/cilastatin, influenza vaccines, ketoconazole, lanreotide, lopinavir, lovastatin, mephenytoin, methicillin, methoxsalen, methylphenidate, methylprednisolone, methyltestosterone, mezlocillin, mizolastine, mycophenolate, nafcillin, nisoldipine, NSAIDs, orlistat, oxacillin, penicillins, phellodendron, phenytoin, pravastatin, prednisolone, prednisone, pristinamycin, ranolazine, red rice yeast, rifabutin, rifampin, rifapentine, ritonavir, rosuvastatin, simvastatin, sirolimus, spironolactone, St John s wort, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfonamides, tacrolimus, telithromycin, tenoxicam, testosterone, ticarcillin, tolvaptan, trabectedin, triamterene, troleandomycin, ursodeoxycholic acid, vaccines, vecuronium, warfarin, zofenopril... 

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