SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid

Pasanen, Marja K.; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko

doi:10.1097/01.fpc.0000230416.82349.90

Cited by 442 publications

(402 citation statements)

References 39 publications

Supporting

Mentioning

373

Contrasting

Unclassified

Order By: Relevance

“…This contrasts with three small studies of pravastatin showing larger effects of rs4149056 on the lipid lowering response [3][4][5]. Simvastatin is given as a lactone prodrug but only the acid form of the drug is transported by OATP1B1 [6]. Pravastatin is given in the acid form so rs4149056 may have a larger effect with pravastatin than with simvastatin.…”

Section: British Journal Of Clinical Pharmacologymentioning

confidence: 43%

The effects of a single nucleotide polymorphism in SLCO1B1 on the pharmacodynamics of pravastatin

Martin

Murray

et al. 2012

Brit J Clinical Pharma

View full text Add to dashboard Cite

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The SNP rs4149056 is associated with altered statin pharmacokinetics and increased risk of statin intolerance. LDL-cholesterol lowering by simvastatin is also affected by rs4149056 but differences between the genotypes are small. Studies of the effect of rs4149056 on pravastatin pharmacodynamics have been inconclusive. WHAT THIS PAPER ADDS• rs4149056 was not associated with an altered lipid or CRP response to 40 mg day -1 pravastatin in more than 600 high risk men from Scotland, suggesting that the rs4149056 genotype does not significantly affect pravastatin efficacy. AIMTo determine whether the SNP rs4149056 in SLCO1B1 alters the pharmacodynamics of pravastatin. METHODSrs4149056 was genotyped in 626 pravastatin-treated participants in the WOSCOPS trial and the response after 1 year of treatment was compared between the different genotypes. RESULTSPravastatin reduced serum LDL cholesterol by 22.2% in TT homozygotes, by 22.2% in TC heterozygotes and by 17.7% in CC homozygotes (TT + TC vs. CC P value 0.33). There were no significant differences in the response of total cholesterol, LDL, HDL, triglycerides or CRP to pravastatin between the genotypes. CONCLUSIONThe rs4149056 SNP did not significantly affect the pharmacodynamics of pravastatin.

show abstract

Section: British Journal Of Clinical Pharmacologymentioning

confidence: 43%

The effects of a single nucleotide polymorphism in SLCO1B1 on the pharmacodynamics of pravastatin

Martin

Murray

et al. 2012

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…For example, it has been reported that carriers of the single nucleotide polymorphism (SNP), c.521T4C (p.Val174Ala), OATP1B1*5 or *15, show increased plasma concentrations of pravastatin, 6-8 repaglinide 9 and simvastatin. 10 Severe toxicity after irinotecanbased chemotherapy for lung cancer has also been reported in a patient with a homozygote for the SLCO1B1*15 allele, which carries the SNP c.521T4C (p.Val174Ala). 11 The SLCO1B1 gene possesses many SNPs and mutations.…”

Section: Introductionmentioning

confidence: 96%

Functional analysis of a mutation in the SLCO1B1 gene (c.1628T>G) identified in a Japanese patient with pravastatin-induced myopathy

et al. 2009

View full text Add to dashboard Cite

In the present study, we analyzed the function of a novel mutation (c.1628T4G, p.Leu543Trp) in the solute carrier organic anion transporter (SLCO) 1B1 gene, encoding organic anion transporting polypeptide (OATP) 1B1, which was identified in a patient with pravastatin-induced myopathy. OATP1B1 variants carrying the mutation (OATP1B1*1a þ c.1628T4G or *1b þ c.1628T4G) showed a reduced transporting activity toward typical substrates and pravastatin compared with the activity of the references (OATP1B1*1a or *1b). This was due to reduction in V max values of the variants, not due to change in their K m values. OATP1B1*1b þ c.1628T4G was normally expressed on the plasma membrane of HEK293 cells at the same level as that of OATP1B1*1b. Taken together, our results suggest that the mutation c.1628T4G (p.Leu543Trp) reduced the function of OATP1B1 probably due to decrease in turnover rate of one OATP1B1 molecule rather than impairment of protein sorting to the plasma membrane.

show abstract

“…The oxidative metabolism of simvastatin acid is catalyzed primarily by CYP3A4 [10] . Additionally, simvastatin and its hydrolysate simvastatin acid are substrates of organic anion transporting polypeptide 1B1 (OATP1B1/Oatp2) [11][12][13][14] , an influx transporter expressed on the sinusoidal membrane of hepatocytes. Recent studies have shown that OATP1B1 plays a clinically important role in the hepatic elimination of several drugs including statins, via mediating the hepatic uptake [11][12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, simvastatin and its hydrolysate simvastatin acid are substrates of organic anion transporting polypeptide 1B1 (OATP1B1/Oatp2) [11][12][13][14] , an influx transporter expressed on the sinusoidal membrane of hepatocytes. Recent studies have shown that OATP1B1 plays a clinically important role in the hepatic elimination of several drugs including statins, via mediating the hepatic uptake [11][12][13][14][15] . Both clinical trials and animal experiments have demonstrated that DM may alter the pharmacokinetic behaviors of some drugs via regulating the expressions and activities of cytochrome P450s (CYP450s) and drug transporters in the liver [16][17][18][19][20][21][22] .…”

Section: Introductionmentioning

confidence: 99%

Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes

Zhang

et al. 2014

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes. Methods: Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR. Results: After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp. Conclusion: Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake.

show abstract

SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid

Cited by 442 publications

References 39 publications

The effects of a single nucleotide polymorphism in SLCO1B1 on the pharmacodynamics of pravastatin

The effects of a single nucleotide polymorphism in SLCO1B1 on the pharmacodynamics of pravastatin

Functional analysis of a mutation in the SLCO1B1 gene (c.1628T>G) identified in a Japanese patient with pravastatin-induced myopathy

Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes

Contact Info

Product

Resources

About