Simvastatin pharmacokinetics

Pasanen, M.K., Neuvonen, M., Neuvonen, P.J. and Niemi, M. (2006) SLCOIBI polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenetics and Genomics, 16, 873-879. 

Sugimoto K, Ohmori M, Tsuruoka S, et al. Different effects of St John s wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Therapeut 2001 70(6) 518-524. 

Interactions with drugs have also been demonstrated for flavonoids from citrus. Naringin and naringenin were shown to interact with simvastatin and saquinavir in in vitro experiments (41,42) and caused alterations in the pharmacokinetics of quinine in rats (44). Moreover, naringenin and naringin were found to inhibit the OATP-B-mediated uptake of estrone-3-sulfate into human embryonic kidney cells (23). 

Increases in exposure were reported for atorvastatin (84,154), lovastatin (155,156), and simvastatin (85,87,157). GFJ was shown not to have an effect on the pharmacokinetics of pravastatin (84,154). Atorvastatin exhibited a moderate interaction with GFJ regarding the overall exposure. Lovastatin and simvastatin exhibited a strong interaction. Pravastatin could be chosen as an alternative drug if patients want to ensure a lack of interaction. 

Lilja JJ, Neuvonen M, Neuvonen PJ. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol 2004 58(l) 56-60. 

Lilja JJ, Kivisto KT, Neuvonen PJ. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther 2000 68(4) 384-390. 

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. 

The effects of itraconazole 200 mg on the pharmacokinetics of simvastatin have been studied in a randomized, double-blind, crossover study in 10 healthy volunteers (47). Itraconazole increased the Cmax and AUC of simvastatin and... 

Dingemanse J. Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Chn Pharmacokinet 2003 42 293-301. 

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. 

O Brien SG et al (2003) Effects of imatinib mesylate (STI571, glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer 89 1855-1859... 

O Brien SG, Peng B, Dutrix C, et al. A pharmacokinetic interaction of Glivec and simvastatin, a cytochrome 3 A substrate, in a patient with chronic myeloid leukemia. Blood 2001 98(suppl) 141a, Abstract 593. 

From an analysis of changes in ciclosporin clearance and systemic availability obtained from the medical records of 100 transplant patients, atorvastatin, fluvastatin, pravastatin, and simvastatin were found to affect ciclosporin pharmacokinetics (228). 

Campana C, lacona I, Regazzi MB, Gavazzi A, Perani G, Raddato V, Montemartini C, Vigano M. Efficacy and pharmacokinetics of simvastatin in heart transplant recipients. Ann Pharmacother 1995 29(3) 235-9. 

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. 

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. 

Hsyu PH, Schultz-Smith MD, Lillibridge JH, Lewis RH, Kerr BM. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001 45(12) 3445-50. 

There has been a study of the effects of ritonavir 400 mg bd plus saquinavir soft-gel capsules 400 mg bd on the pharmacokinetics of pravastatin, simvastatin, and atorvas-tatin (40 mg/day each), and of the effect of pravastatin on the pharmacokinetics of nelfinavir in a randomized, open study in 56 healthy HIV-negative adults (46). Ritonavir - -saquinavir reduced the steady-state AUC of pravastatin, markedly increased the AUC of simvastatin, and slightly increased the AUC of total active atorvastatin. The AUCs of nelfinavir and its active M8 metabolite were not altered by pravastatin. The authors concluded that simvastatin (and by implication lovastatin, which in... 

The effects of a combination of erythromycin and verapamil on the pharmacokinetics of a single dose of simvastatin have been studied in a randomized, double-blind, cross-over study in 12 healthy volunteers simultaneously taking the three drugs. Both erythromycin and verapamil interacted with simvastatin, producing significant increases in the serum concentrations of simvastatin and its active metabolite simvastatin acid. The mean C ax of active simvastatin acid was increased about five-fold and the AUCo 24 four-fold by erythromycin verapamil increased the C ax of simvastatin acid 3.4-fold and the AUCo 24 2.8-fold. There was a substantial interindividual variation in the extent of these interactions. Concomitant use of erythromycin, verapamil, and simvastatin should be avoided (35). 

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... 

Keskitalo JE, Pasanen MK, Neuvonen PJ, Niemi M (2009) Different effects of the ABCG2 c.421C>A SNP on the pharmacokinetics of fluvastatin, pravastatin and simvastatin. Pharmacogenomics 10 1617-1624... 

---