Metabolism atorvastatin

It s apparent that CYPs are involved in the metabolism of all but one, Plavix (clopido-grel), and even for that compound they re important downstream, after initial hydrolysis of the ester. What s not apparent from the figure is that metabolism isn t always something that limits drug effectiveness. Some drugs like valsartan are mostly excreted unchanged, while for others, like the top-seller Lipitor (atorvastatin) metabolism affords compounds that are still active. In Lipitor s case, active metabolites are said to account for 70% of the pharmacodynamic (PD) effect the drug produces. Much more worrisome would be reactive (electrophilic) metabolites that make for toxicity or metabolites that affect GYP expression or function. 

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. 

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. 

While rhabdomyolysis from statins is rare, the risk is increased when they are used in combination with agents that share similar metabolic pathways. Atorvastatin is metabolized by CYP3A4, which is inhibited by diltiazem. 

Atorvastatin is readily absorbed after the oral administration. Multiple daily dosages in the form of 2.5-80 mg capsules produce a maximum steady state concentration (Cmax) of 1.95-252 /ig/ml within 1-2 h. The AUC increases in proportion to the dose of atorvastatin, but the increase in Cmax is greater than for the proportional dose. The low systemic availability is attributed to the presystemic clearance in gastrointestinal mucosa and/or hepatic first pass metabolism. Food significantly... 

Atorvastatin is extensively metabolized to its ortho- and para-hyd roxylated derivatives, and to various beta oxidation products. At least 70% of HMG-CoA reductase inhibitory activity has been attributed to the active metabolites of atorvastatin. 

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. 

Midazolam is metabolized by CYP3A4, as is atorvastatin. In a matched-pair study the effects of long-term atorvastatin on the pharmacokinetics of midazolam 0.15 mg/kg intravenously as a single dose were studied in 14 patients undergoing general anesthesia for elective surgery (56). Atorvastatin significantly reduced the clearance of midazolam by 33% and increased the AUC by 40%. 

Atorvastatin is absorbed well but is subject to extensive first-pass metabolism in the gut wall and the liver, converting it to active metabolites that are responsible for 70% of its clinical activity [19, 22]. 

Atorvastatin and simvastatin are primarily metabolized by CYP3A4, They are both transported by P-gp, and atorvastatin is also transported by OATP1B1, Fluvastatin is metabolized primarily by CYP2C9. Pravastatin has not been shown to be metabolized by CYP3A4 to a clinically significant degree, although it is enzymatically broken down in the liver, Nor is pravastatin a known substrate of P-gp. 

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- ATORVASTATIN, LOVASTATIN, ROSUVASTATIN, SIMVASTATIN CICLOSPORIN t plasma concentrations of these statins, with risk of myopathy and rhabdomyolysis Cidosporin is a moderate inhibitor of CYP3A4, which metabolizes these statins 1 statins to lowest possible dose (do not give simvastatin in doses >10 mg). Monitor LFTs and CK closely warn patients to report any features of rhabdomyolysis. This interaction does not occur with pravastatin... 

ATORVASTATIN PROTEASE INHIBITORS t efficacy and t risk of adverse effects of atorvastatin Inhibition of CYP3A4-mediated metabolism of atorvastatin Use with caution monitor for atorvastatin toxicity monitor CK. Inform patient and 1 dose if necessary or start with 10 mg once daily. Use the lowest dose possible to attain target low-density lipoprotein reduction. Alternatives are pravastatin orfluvastatin... 

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... 

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