Lovastatin, metabolism

It has been suggested that danazol (and the doxycycline) were possibly hepatotoxic, which led to decreased lovastatin metabolism, or that the danazol had a direct toxic effect on the muscles. Efanazol inhibits the cytochrome P450 isoenzyme CYP3A4 by which simvastatin and lovastatin are metabolised, which would result in raised statin levels, and therefore myopathy and rhabdomyolysis. This seems a more likely explanation for the effects seen. 

A prodrag is a drug that is not by itself pharmacologically active but needs metabolic activation by an enzyme. Examples are the cytostatic cyclophosphamide, which is activated by hydroxylation catalyzed by CYP2B6, or HMGCoA reductase inhibitor, lovastatin, which contains... 

K., Benet, L. Z., Sewing, K. F., Christians, U., Small intestinal metabolism of the 3-hydroxy-3-mefhylglutaryl-coenzyme A reductase inhibitor lovastatin and comparison with pravastatin, /. Pharmacol. Exp. Ther. 1999, 291, 131-139. 

Sanllehy C, Casals E, Rodriguez-Vil-lar C, Zambon D, Ojuel J, Ballesta AM, et al. Lack of interaction of apolipo-protein E phenotype with the lipoprotein response to lovastatin or gemfibrozil in patients with primary hypercholesterolemia. Metabolism 1998 47 560-565. 

Of all N Rs involved in xenobiotics metabolism induction, PX R is the most prominent one. PXR functions as a xenobiotic sensor and is activated by a large variety of chemically diverse compounds, for example lovastatin, nifedipine, rifampicin, SR12813, troglitazone or hyperforin (Chart 14.3), many of them standard therapeutic agents for common diseases [20-25]. 

The pharmacokinetic implications of these findings are not straightforward. One important factor that must also be considered is hepatic extraction, which is higher for lovastatin than for its hydroxy acid metabolite [188], Some lactones are useful prodrugs of HMG-CoA reductase inhibitors due to this organ selectivity coupled with the efficiency of enzymatic hydrolysis. However, other factors may also influence the therapeutic response, in particular the extent and rate of metabolic reactions that compete with or follow hydrolysis, e.g., cytochrome P450 catalyzed oxidations, /3-oxidation, and tau-... 

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. 

Lovastatin and 4-phenylbutyrate are being tested as new therapeutic approaches to stimulate VLCFA metabolism. 

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)... 

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

An important dmg in the regulation of cholesterol metabolism is lovastatin [75330-75-5] which is an HMG—CoA reductase inhibitor (see Cardiovascularagents). p-Hydroxy-p-methyl glutarate—coenzyme A (HMG—CoA) reductase is the rate-limiting enzyme of cholesterol synthesis. Lovastatin is actually a prodmg, which is eventually hydrolyzed in the liver to its active, p-hydroxylated form (5). 

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. 

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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