SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid.

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Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M

SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid.

Pharmacogenet Genomics. 2006 Dec;16(12):873-9. doi: 10.1097/01.fpc.0000230416.82349.90.

PubMed ID

17108811 [ View in PubMed

]

Abstract

BACKGROUND AND OBJECTIVE: Organic anion transporting polypeptide 1B1 (OATP1B1) is an uptake transporter located at the sinusoidal membrane of human hepatocytes. This study aimed to investigate the effects of genetic polymorphism in the SLCO1B1 gene encoding OATP1B1 on the pharmacokinetics of simvastatin. METHODS: Four healthy volunteers with the homozygous SLCO1B1 c.521CC genotype, 12 with the heterozygous c.521TC genotype and 16 with the homozygous c.521TT genotype (controls) were recruited. Each study participant ingested a single 40-mg dose of simvastatin. Plasma concentrations of simvastatin (inactive lactone) and its active metabolite simvastatin acid were measured for 12 h. RESULTS: The AUC0-infinity of simvastatin acid was 120 and 221% higher in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TC and c.521TT (reference) genotypes, respectively (P<0.001). The Cmax of simvastatin acid was 162 and 200% higher in participants with the c.521CC genotype than in those with the c.521TC and c.521TT genotypes (P<0.001). The Cmax of simvastatin acid occurred earlier in participants with the c.521CC and c.521TC genotypes than in those with the c.521TT genotype (P<0.05). No association existed between the SLCO1B1 genotype and the elimination half-life of simvastatin acid. Moreover, no statistically significant association was seen between the SLCO1B1 genotype and the pharmacokinetics of simvastatin lactone. CONCLUSIONS: SLCO1B1 polymorphism markedly affects the pharmacokinetics of active simvastatin acid, but has no significant effect on parent simvastatin. Raised plasma concentrations of simvastatin acid in patients carrying the SLCO1B1 c.521C variant allele may enhance the risk of systemic adverse effects during simvastatin treatment. In addition, reduced uptake of simvastatin acid by OATP1B1 into the liver in patients with the c.521C allele could reduce its cholesterol-lowering efficacy.

DrugBank Data that Cites this Article

Drugs

Simvastatin

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Simvastatin	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Substrate Inhibitor	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Atorvastatin Clarithromycin	The risk or severity of rhabdomyolysis can be increased when Clarithromycin is combined with Atorvastatin.
Lovastatin Clarithromycin	The risk or severity of myopathy and rhabdomyolysis can be increased when Clarithromycin is combined with Lovastatin.
Pravastatin Erythromycin	The risk or severity of myopathy and rhabdomyolysis can be increased when Erythromycin is combined with Pravastatin.
Pravastatin Clarithromycin	The serum concentration of Pravastatin can be increased when it is combined with Clarithromycin.
Simvastatin Clarithromycin	The serum concentration of Simvastatin can be increased when it is combined with Clarithromycin.