Statins pharmacokinetics

Healthy volunteers were given protease inhibitors and statins, and the authors concluded that simvastatin should be avoided and that atorvastatin could be used with caution in people taking ritonavir and saquinavir (111). Dosage adjustment of pravastatin may be necessary with co-administration of ritonavir and saquinavir. Pravastatin does not alter the pharmacokinetics of nelfinavir, and thus appears to be safe for co-administration. 

A. Corsini, S. Bellosta, R. Baetta, R. Fumagalli, R. Paoletti, F. Bernini, New insights into the pharmacodynamic and pharmacokinetic properties of statins, Pharmacol. Ther. 84 (1999) 413-428. 

Ballantine CM, Davidson MH. Possible differences between fibrates in pharmacokinetic interactions with statins. Arch. Intern. Med., 2003, 163, 2394. 

Based on their pharmacokinetic profile alone, the safest statins in chronic compensated liver disease and a history of decompensation are prohahly pravastatin and rosnvastatin. However, clinical experience with rosnvastatin in liver disease is lacking, and so it cannot be recommended. In addition, the true rate of post-marketing adverse drug reactions is not yet clear. Pravastatin is therefore the drug of choice in these patients, where treatment is deemed necessary. It should, however, be avoided in acute episodes until liver function or transaminases stabilise/return to normal. 

The hydrophilic statins (pravastatin, rosuvastatin) are only partly metabolised by the liver [1, 17, 19]. Pravastatin is also metabolised in the stomach [26]. The pharmacokinetics of pravastatin have been shown to change in liver disease, despite its dual route (renal and hepatic) of elimination [27]. Nonetheless, it has been used in liver disease and has been suggested as the statin of choice [26]. Liver metabolism is of minor importance in the clearance of rosuvastatin and its pharmacokinetics are not altered by mild to moderate liver impairment. However, the area under the curve (AUC) is increased in severe liver impairment [1]. Clinical experience with rosuvastatin in liver disease is lacking, and it therefore cannot be recommended. 

Corsini A, Bellosta S, Davidson MH (2005) Pharmacokinetic interactions between statins and fibrates. Am J Cardiol 96 44K-9K. 

Herman RJ (1999) Drug interactions and the statins. CMAJ 161 1281-1286. Schachter M (2005) Chemical, pharmacokinetic and pharmacodynamic properties of statins an update. Fund Clin Pharmacol 19 117-125. 

An example of the former case (drug A behavior) is illustrated in the effect of food on the PK and the PD of pravastatin, a representative statin in the treatment of hyperlipidemia. Although a low-fat, low-cholesterol meal altered the pharmacokinetics of 20-mg pravastatin significantly, no adverse impact on pharmacodynamics... 

The effects of statins on the pharmacokinetics of digoxin have been variable. There is no simple explanation that reconciles the disparate findings. 

Dosages of statins should be reduced in patients taking ciclosporin, because of pharmacodynamic and pharmacokinetic interactions. 

It has been proposed that the risk of myotoxicity increases when statins are prescribed concurrently with erythromycin (83). There are no data for any pharmacokinetic interaction with fluvastatin or pravastatin, but as in the case of simvastatin the major route of metabolism of these drugs is by CYP3A4 and there is potential for an adverse interaction. 

The increased risk of myopathy observed during concomitant treatment with statins and fibrates may be partly pharmacokinetic in origin. In interactions between fibrates and statins there may be differences between... 

It has been suggested that the pharmacokinetics of fluvastatin, including extensive biliary excretion and absence of circulating active metabolites, might be associated with a low incidence of systemic adverse effects compared with other statins. In over 1800 patients treated for an average of 61 weeks, fluvastatin was safe and tolerable (SEDA-19, 408). Pooled data from clinical trials have shown that gastrointestinal symptoms occurred in 14% of fluvastatin recipients compared with 9% taking placebo other complaints occurred... 

Neuvonen PJ, Backman JT, Niemi M (2008) Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin. Clin Pharmacokinet 47 463 74... 

Chien KL, Wang KC, Chen YC, Chao CL, Hsu HC, Chen MF, Chen WJ (2010) Common sequence variants in pharmacodynamic and pharmacokinetic pathway-related genes conferring LDL cholesterol response to statins. Pharmacogenomics 11 309-317... 

Statins differ in their pharmacokinetic properties and in pleotropic effects (i.e., non-lipid-lowering). The contribution of lipid lowering alone (a class effect) versus other effects (anti-inflammatory, antithrombotic, etc.) continues to create controversy. 

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