Subject simvastatin

In 18 healthy subjects simvastatin 40 mg once daily had no effect on the pharmacokinetics of eplerenone 100 mg once daily. The maximum level of simvastatin was modestly decreased by 32%, and the AUC by 14%, but this was not considered to be clinically relevant. ... 

The statins, lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) resembles that of the physiological substrate of the enzyme (A). L and S are lactones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metabolites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective hepatic uptake of the mycotoxin, amanitin (A), Atorvastatin has the longest duration of action. 

Sugimoto et al. examined the effect of St. John s wort administration (300 mg three times a day for 14 days) on the disposition of simvastatin and pravastatin in 16 healthy male Japanese subjects in a double-blind crossover study (104). The administration of St. John s wort significantly... 

Some studies have shown increased risks of violent death and depression in subjects with reduced serum cholesterol concentrations. Serum and membrane cholesterol concentrations, the microviscosity of erythrocyte membranes, and platelet serotonin uptake have been determined in 17 patients with hypercholesterolemia (21). There was a significant increase in serotonin transporter activity only during the first month of simvastatin therapy. This suggests that within this period some patients could be vulnerable to depression, violence, or suicide. This is an important paper, in that it explains why mood disorders are not regularly seen in clinical trials with statins, as has been summarized in a recent review (3). 

Eckernas SA, Roos BE, Kvidal P, Eriksson LO, Block GA, Neafus RP, Haigh JR. The effects of simvastatin and pravastatin on objective and subjective measures of nocturnal sleep a comparison of two structurally different HMG CoA reductase inhibitors in patients with primary moderate hypercholesterolaemia. Br J Clin Pharmacol 1993 35(3) 284-9. 

A small well-designed study in 14 healthy subjects showed no significant effect of irbesartan on the single-dose pharmacokinetics of total simvastatin acid (7). 

Marino MR, VachharajaniNN, HadjUambris OW. Irbesartan does not affect the pharmacokinetics of simvastatin in healthy subjects. J Clin Pharmacol 2000 40(8) 875-9. 

D4. De Caterina, R., Cipollone, F., Filardo, F. P., Zimarino, M., Bernini, W., Lazzerini, G., Bucciarelli, T., Falco, A., Marchesani, P., Muraro, R., Mezzetti, A., and Ciabattoni, G., Low-density lipoprotein level reduction by the 3-hydroxy-3-methylglutaryl coenzyme-A inhibitor simvastatin is accompanied by a related reduction of F2-isoprostane formation in hypercholesterolemic subjects No further effect of vitamin E. Circulation 106, 2543-2549 (2002). 

A study in 30 healthy subjects found that single and multiple doses of amlodipine 10 mg for 15 days (with or without lisinopril and simvastatin) had no effect on the pharmacokinetics of alcohol 0.8 g/kg nor on subjective psychological performance. Alcohol did not alter the pharmacokinetics of amlodipine. ... 

A three-period, erossover, open-label study in healthy subjects found that simvastatin 20 mg daily increased the maximum plasma level of repaglinide 2 mg three times daily by 26%, although there was high variability and the mean bioavailability of repaglinide was increased by 8%. There was a higher ineidenee of adverse effeets during concurrent use. ... 

A single 1-g oral dose of tolbutamide was given to two groups of 16 healthy subjects taking fluvastatin 40 mg or simvastatin 20 mg. The pharmacokinetics of the tolbutamide were affected only to a very minor extent, and the blood glucose-lowering effects of the tolbutamide were unchanged." ... 

However, in a study in healthy subjects, pioglitazone 45 mg daily did not significantly affect the pharmacokinetics of simvastatin 80 mg daily and concurrent use was well tolerated. Similarly, there was no pharmacokinetic interaction between pioglitazone 45 mg daily and atorvastatin 80 mg daily Moreover, clinical use of rosiglitazone with atorvastatin in patients with type 2 diabetes for 16 weeks was well tolerated, as was the clinical use of rosiglitazone or pioglitazone with simvastatin."... 

Jerling M, Huan B-L, Leung K, Chu N, Abdallah H, Hussein Z. Studies to investigate die pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem or simvastatin during combined administration in healthy subjects. J Clin Pharmacol. (2005) 45, 422-33. 

A study in 12 healthy subjects found that irbesartan 300 mg had no significant effect on the pharmacokinetics of a single 50-mg dose of simvastatin, or its metabolite simvastatin acid, and the combination was well-tolerated. No clinically relevant interaction was noted when telmisartan was given with simvastatin. ... 

In a two-phase crossover study, 10 healthy subjects were given itraconazole 200 mg daily or a placebo for 4 days, with a single 40-mg dose of simvastatin on day 4. The peak serum level s of total simvastatin acid (simvastatin acid plus simvastatin lactone) were increased 17-fold and the AUC was increased 19-fold. The maximum serum levels and the AUC of total HMG-CoA reductase inhibitors increased about 3-fold and 5-fold, respectively. ... 

Diitiazem. A single 20-mg dose of simvastatin was given to 10 healthy subjects after they had taken sustained-release diltiazem 120 mg twice daily for 2 weeks. Diltiazem caused about a fivefold increase in the simvastatin AUC, a fourfold increase in the maximum serum levels, and a 2.5-fold increase in the half-life."... 

Verapamil. A study in which 12 subjects were given verapamil 80 mg three times daily, found a 4.6-fold increase in the AUC of simvastatin, a 2.6-fold increase in its maximum serum levels, and about a twofold increase in its half-life. Similarly, a study in 12 healthy subjects found that extended-release verapamil 480 mg daily for 3 days caused a fivefold increase in the maximum serum levels of simvastatin 40 mg, and about a fourfold increase in its AUC. ... 

In a randomised, crossover study 12 healthy subjects were given carbamazepine 200 mg daily for 2 days, then 300 mg twice daily for 12 days, with a single 80-mg dose of simvastatin 12 hours after the last dose of carbamazepine. The AUC and maximum serum levels of simvastatin were reduced by 75% and 68%, respectively, and the AUC and maximum serum levels of simvastatin acid (the active metabolite of simvastatin) were reduced by 82% and 69%, respectively. ... 

In a randomised, erossover study 25 healthy subjects were given simvastatin 80 mg daily with fenofibrate 160 mg daily for 7 days. The phaima-cokineties of both drugs and their main metabolites (as assessed in 12 subjeets) were unchanged by concurrent use. All 25 subjects were assessed for safety, and the combination was found to be well tolerated. ... 

In a randomised study 3 groups of 15 healthy subjects were given atorvastatin 80 mg daily, pravastatin 40 mg daily or simvastatin 40 mg daily with clarithromycin 500 mg twice daily for 8 days. Clarithromycin increased the AUC of atorvastatin by fourfold, pravastatin by twofold and simvastatin by tenfold. ... 

In an open label study, 31 healthy subjects were given either atorvastatin 10 mg daily or simvastatin 20 mg daily for 28 days, with nelfinavir 1.25 g twice daily for the last 14 days. Nelfinavir increased the maximum serum levels and AUC of atorvastatin approximately twofold and the maximum serum levels and AUC of simvastatin approximately sixfold. No significant adverse effects, or any signs of rhabdomyolysis were noted throughout the study. ... 

Ritonavir 300 mg twice daily and saquinavir 400 mg twice daily were given to healthy subjects for 3 days, after which the dose was increased to ritonavir 400 mg twice daily and saquinavir 400 mg twice daily for a further 11 days. On the last 4 days atorvastatin, pravastatin, or simvastatin (all 40 mg daily) were also given. The mean pravastatin AUC was approximately halved (13 subjects), the mean atorvastatin AUC was increased approximately fourfold (14 subjects) and the mean simvastatin acid AUC was increased approximately 32-fold (14 subjects). No cases of rhabdomyolysis were noted. ... 

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