Mikko Neuvonen

SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid.

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–∞ 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.

Polymorphic Organic Anion Transporting Polypeptide 1B1 is a Major Determinant of Repaglinide Pharmacokinetics

A large interindividual variability exists in the plasma concentrations of repaglinide. Our aim was to investigate possible associations between the pharmacokinetics of repaglinide and single nucleotide polymorphisms (SNPs) in the genes encoding for the drug transporters organic anion transporting polypeptide 1B1 (OATP1B1) (SLCO1B1) and P‐glycoprotein (MDR1, ABCB1) and the drug‐metabolizing enzymes cytochrome P450 (CYP) 2C8 and CYP3A5.

Gemfibrozil greatly increases plasma concentrations of cerivastatin.

Concomitant use of gemfibrozil with statins, particularly with cerivastatin, increases the risk of rhabdomyolysis, but the mechanism of this potentially fatal drug interaction remains unclear. Our aim was to study the effect of gemfibrozil on cerivastatin pharmacokinetics.

Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate

Concomitant use of fibrates with statins has been associated with an increased risk of myopathy, but the underlying mechanism of this adverse reaction remains unclear. Our aim was to study the effects of bezafibrate and gemfibrozil on the pharmacokinetics of lovastatin.

Cyclosporine markedly raises the plasma concentrations of repaglinide

Repaglinide is an antidiabetic drug metabolized by cytochrome P450 (CYP) 2C8 and 3A4, and it appears to be a substrate of the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1). We studied the effects of cyclosporine (INN, ciclosporin), an inhibitor of CYP3A4 and OATP1B1, on the pharmacokinetics and pharmacodynamics of repaglinide.

Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance.

Background: Gemfibrozil increases the plasma concentrations of active acid forms of cerivastatin, lovastatin, and simvastatin. Pravastatin pharmacokinetics differs from those of these 3 statins, which are extensively metabolized. Our aim was to study the effects of gemfibrozil on the pharmacokinetics of pravastatin.

Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide

Our objective was to investigate the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C8 on the pharmacokinetics and pharmacodynamics of the meglitinide analog antidiabetic drug repaglinide.

Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations

Rifampin (rifampicin) is a potent inducer of several cytochrome P450 (CYP) enzymes, including CYP3A4. The cholesterol‐lowering drug simvastatin has an extensive first‐pass metabolism, and it is partially metabolized by CYP3A4. This study was conducted to investigate the effect of rifampin on the pharmacokinetics of simvastatin.

Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites

The pharmacokinetic interactions of the widely used statin atorvastatin with fibrates and enzyme inducers are not known. Therefore we studied the effects of rifampin (INN, rifampicin) and gemfibrozil on the pharmacokinetics of atorvastatin.

Effects of rifampin on the pharmacokinetics and pharmacodynamics of glyburide and glipizide.

To study the effects of rifampin (INN, rifampicin) on the pharmacokinetics and pharmacodynamics of glyburide (INN, glibenclamide) and glipizide, 2 sulfonylurea antidiabetic drugs.