Pharmacokinetic interactions between glimepiride and rosuvastatin in healthy Korean subjects: does the <em>SLCO1B1</em> or <em>CYP2C9</em> genetic polymorphism affect these drug interactions?

Abstract

To improve cardiovascular outcomes, dyslipidemia in patients with diabetes needs to be treated. Thus, these patients are likely to take glimepiride and rosuvastatin concomitantly. Therefore, this study aimed to evaluate the pharmacokinetic (PK) interactions between these two drugs in healthy males and to explore the effect of SLCO1B1 and CYP2C9 polymorphisms on their interactions in two randomized, open-label crossover studies. Glimepiride was studied in part 1 and rosuvastatin in part 2. Twenty-four participants were randomly assigned to each part. All subjects (n=24) completed part 1, and 22 subjects completed part 2. A total of 38 subjects among the participants of the PK interaction studies were enrolled in the genotype study to analyze their SLCO1B1 and CYP2C9 polymorphisms retrospectively (n=22 in part 1, n=16 in part 2). Comparison of the PK and safety of each drug alone with those of the drugs in combination showed that both glimepiride and rosuvastatin did not interact with each other and had tolerable safety profiles in all subjects. However, with regard to glimepiride PK, the SLCO1B1 521TC group had a significantly higher maximum plasma concentration (Cmax,ss) and area under the plasma concentration–time curve during the dose interval at steady state (AUCτ,ss) for glimepiride in combination with rosuvastatin than those for glimepiride alone. However, other significant effects of the SLCO1B1 or CYP2C9 polymorphism on the interaction between the two drugs were not observed. In conclusion, there were no significant PK interactions between the two drugs; however, the exposure to glimepiride could be affected by rosuvastatin in the presence of the SLCO1B1 polymorphism.

Association between SLCO1B1 polymorphism distribution frequency and blood lipid level in Chinese adults

“…OATP1B1 has a role in the transport of a wide variety drugs, such as statins. Several pharmacogenetic studies and metaanalyses have focused on the potential contribution of SLCO1B1 variations in the response to statins or repaglinide, but little attention has been paid to whether SLCO1B1 is involved in lipoprotein transformation and metabolic process that affects individual lipid levels [4][5][6][7][8][9][10][11][12][13][14][15]. We therefore hypothesised that common variants of SLCO1B1 have an impact into levels of serum lipids, and so by extension, a potential role in risk assessment.…”

Pharmacokinetic interactions between glimepiride and rosuvastatin in healthy Korean subjects: does the SLCO1B1 or CYP2C9 genetic polymorphism affect these drug interactions? Observations and introspection of the bioanalysis

“…Recently, Kim et al demonstrated a well-planned and meticulously executed clinical investigation to understand the role of SLCO1B1 or CYP2C9 genetic polymorphism on the pharmacokinetics of glimepiride and rosuvastatin in healthy Korean subjects 4. Most importantly, the pharmacokinetic interaction study consisted of two parts: parts 1 and 2.…”

“…Recently, Kim et al demonstrated a well-planned and meticulously executed clinical investigation to understand the role of SLCO1B1 or CYP2C9 genetic polymorphism on the pharmacokinetics of glimepiride and rosuvastatin in healthy Korean subjects. 4 Most importantly, the pharmacokinetic interaction study consisted of two parts: parts 1 and 2. Part 1 was designed to evaluate the effect of rosuvastatin on the pharmacokinetics of glimepiride and part 2 was designed to determine the effect of glimepiride on the pharmacokinetics of rosuvastatin.…”

“…Blood samples were collected at predetermined time points and samples were analyzed using liquid chromatography-mass spectrometer to determine the drug concentration in the plasma samples. 4 …”

“…For analysis of rosuvastatin and N -desmethyl rosuvastatin, the authors took 50 µL of plasma and mixed with 10 µL of valsartan, an internal standard (100 ng/mL in 50% acetonitrile). 4 The mixture was centrifuged, followed by the collection of supernatant, which was evaporated till dryness and reconstituted in 200 µL of 50% acetonitrile for analysis. 4 From the process detailed by the authors, it is evident that the authors wanted to deproteinize the plasma samples using 50% acetonitrile containing the internal standard.…”