스타틴계 약물의 체내동태에 미치는 유기음이온 수송계 SLCO1B1의 영향 : The Effect of SLCO1B1 on the Disposition of Statins : the Genetic Polymorphisms of SLCO1B1 and Transporter-Mediated Drug-Drug Interaction Involving SLCO1B1 : SLCO1B1의 유전적 다형성 및 SLCO1B1에 의한 약물상호작용 연구원문보기
목적 : 음이온 수송계인 OATP1B1을 인코드하는 SLCO1B1 유전자의 변이형, 특히 SLCO1B1*15/*15 유전형은 HMG-CoA reductase inhibitor인 statin 계열의 체내동태에 영향을 미치는 것으로 알려져 있다. Pravastatin은 수용성...
목적 : 음이온 수송계인 OATP1B1을 인코드하는 SLCO1B1 유전자의 변이형, 특히 SLCO1B1*15/*15 유전형은 HMG-CoA reductase inhibitor인 statin 계열의 체내동태에 영향을 미치는 것으로 알려져 있다. Pravastatin은 수용성이며 OATP1B1에대한 친화성이 낮은 기질약물이나, pitavastatin은 지용성이 크고, OATP1B1에대한 친화성이 큰 기질약물이다. 그러므로, 본 연구에서는 pravastatin과 pitavastatin의 체내동태에 대한 OATP1B1 수송계의 유전다형의 영향을 조사하고, 이를 두 기질 약물의 지용성과 in vitro 수송활성의 측면에서 고찰하고자 하였다.
방법 : 494개 DNA 샘플의 유전형을 PCR-RFLP법과 pyrosequencing법을 이용하여 분석하였다. 유전형 분석과 건강 진단을 통하여 SLCO1B1*1a/*1a (n=6)과 SLCO1B1*15/*15 (n=5)의 두 그룹을 선정하고 균형 라틴격자방식의 2원 교차실험 설계 하에 40mg pravastatin과 4mg pitavastatin을 투약한 뒤 48시간 동안 채혈하였다. SLCO1B1*1a와 SLCO1B1*15을 과발현시킨 개구리알에서 pravastatin, pitavastatin, fluvastatin의 농도별 uptake 실험을 수행하였으며, 혈중 및 개구리알 내의 pravastatin, pitavastatin 및 fluvastatin 의 농도는 LC/MS/MS로 분석하였다.
목적 : 음이온 수송계인 OATP1B1을 인코드하는 SLCO1B1 유전자의 변이형, 특히 SLCO1B1*15/*15 유전형은 HMG-CoA reductase inhibitor인 statin 계열의 체내동태에 영향을 미치는 것으로 알려져 있다. Pravastatin은 수용성이며 OATP1B1에대한 친화성이 낮은 기질약물이나, pitavastatin은 지용성이 크고, OATP1B1에대한 친화성이 큰 기질약물이다. 그러므로, 본 연구에서는 pravastatin과 pitavastatin의 체내동태에 대한 OATP1B1 수송계의 유전다형의 영향을 조사하고, 이를 두 기질 약물의 지용성과 in vitro 수송활성의 측면에서 고찰하고자 하였다.
방법 : 494개 DNA 샘플의 유전형을 PCR-RFLP법과 pyrosequencing법을 이용하여 분석하였다. 유전형 분석과 건강 진단을 통하여 SLCO1B1*1a/*1a (n=6)과 SLCO1B1*15/*15 (n=5)의 두 그룹을 선정하고 균형 라틴격자방식의 2원 교차실험 설계 하에 40mg pravastatin과 4mg pitavastatin을 투약한 뒤 48시간 동안 채혈하였다. SLCO1B1*1a와 SLCO1B1*15을 과발현시킨 개구리알에서 pravastatin, pitavastatin, fluvastatin의 농도별 uptake 실험을 수행하였으며, 혈중 및 개구리알 내의 pravastatin, pitavastatin 및 fluvastatin 의 농도는 LC/MS/MS로 분석하였다.
Objectives . Genetic variants of the organic anion transporting polypeptide 1B1 (OATP1B1) (SLCO1B1 gene), in particular SLCO1B1*15/*15 genotype, have been associated with changes in the pharmacokinetics of statins in humans. Pravastain is a hydrophilic substrate of OATP1B1 with low affinity (i.e., t...
Objectives . Genetic variants of the organic anion transporting polypeptide 1B1 (OATP1B1) (SLCO1B1 gene), in particular SLCO1B1*15/*15 genotype, have been associated with changes in the pharmacokinetics of statins in humans. Pravastain is a hydrophilic substrate of OATP1B1 with low affinity (i.e., the Km value: 85.7 mM) and pitavastatin is a lipophilic substrate with high affinity (i.e., the Km value: 3.0 mM). This study was addressed to understand the underlying mechanism of the substrate dependent effect of genetic variation in SLCO1B1, which encodes OATP1B1 transporter, on the disposition of two OATP1B1 substrates, pravastatin and pitavastatin, in relation to their transport activities.
Methods The uptake of pravastatin, pitavastatin, and fluvastatin was measured in oocytes overexpressing SLCO1B1*1a and SLCO1B1*15 to compare the alterations of in vitro transporting activity. 494 human DNA samples were genotyped and Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and Pyrosequencing were used to identify OATP1B1*1a (wild type), OATP1B1*1b (Asn130Asp,A388G), OATP1B1*5(Val174Ala,T521C) and OATP1B1*15(A388G and T521C). The following genotyping groups were studied: subjects with homozygous variants SLCO1B1*15/*15 (n=5); subjects with homozygous variants SLCO1B1*1a/*1a (n=6). After 40mg pravastatin or 4mg pitavastatin was administered to the eleven healthy volunteers with homozygous genotypes of SLCO1B1*1a/*1a and SLCO1B1*15/*15, the pharmacokinetic parameters of pravastatin and pitavastatin were compared among subjects with SLCO1B1*1a/*1a and SLCO1B1*15/*15 genotypes.
Results The uptake of pravastatin and pitavastatin in SLCO1B1*15 overexpressing oocytes was decreased compared with that in SLCO1B1*15, but no change occurred with fluvastatin. The fold change of in vitro Clint for pitavastatin in SLCO1B1*15 compared to SLCO1B1*1a was larger than that of pravastatin (p<0.0001). The Cl/F of pitavastatin was decreased to a greater degree in subject with SLCO1B1*15/*15 compared to that of pravastatin in vivo (p<0.01), consistent with in vitro study. As a result, Cmax and AUC of these non-metabolized substrates were increased by SLCO1B1*15 variant. However, the greater decrease in the transport activity for pitavastatin in SLCO1B1*15 variant compared to SLCO1B1*1a was associated with the greater effect on the pharmacokinetics of pitavastatin compare to pravastatin in relation to the SLCO1B1 genetic polymorphism.
Conclusions The fold changes in major pharmacokinetic parameters of pitavastatin in subjects with OATP1B1*15/*15 compared to OATP1B1*1a/*1a were larger than those of pravastatin. Considering the lipophilicity and higher affinity to the OATP1B1 transporter of pitavastatin, physicochemical properties and in vitro transporter activity may contribute the different effect of OAPT1B1 polymorphism on the pharmacokinetics of pravastatin and pitavastatin, and it suggested that substrate dependency in the consequences of the SLCO1B1*15 variant could modulate the effect of SLCO1B1 polymorphism on the disposition of pitavastatin and pravastatin.
Objectives . Genetic variants of the organic anion transporting polypeptide 1B1 (OATP1B1) (SLCO1B1 gene), in particular SLCO1B1*15/*15 genotype, have been associated with changes in the pharmacokinetics of statins in humans. Pravastain is a hydrophilic substrate of OATP1B1 with low affinity (i.e., the Km value: 85.7 mM) and pitavastatin is a lipophilic substrate with high affinity (i.e., the Km value: 3.0 mM). This study was addressed to understand the underlying mechanism of the substrate dependent effect of genetic variation in SLCO1B1, which encodes OATP1B1 transporter, on the disposition of two OATP1B1 substrates, pravastatin and pitavastatin, in relation to their transport activities.
Methods The uptake of pravastatin, pitavastatin, and fluvastatin was measured in oocytes overexpressing SLCO1B1*1a and SLCO1B1*15 to compare the alterations of in vitro transporting activity. 494 human DNA samples were genotyped and Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and Pyrosequencing were used to identify OATP1B1*1a (wild type), OATP1B1*1b (Asn130Asp,A388G), OATP1B1*5(Val174Ala,T521C) and OATP1B1*15(A388G and T521C). The following genotyping groups were studied: subjects with homozygous variants SLCO1B1*15/*15 (n=5); subjects with homozygous variants SLCO1B1*1a/*1a (n=6). After 40mg pravastatin or 4mg pitavastatin was administered to the eleven healthy volunteers with homozygous genotypes of SLCO1B1*1a/*1a and SLCO1B1*15/*15, the pharmacokinetic parameters of pravastatin and pitavastatin were compared among subjects with SLCO1B1*1a/*1a and SLCO1B1*15/*15 genotypes.
Results The uptake of pravastatin and pitavastatin in SLCO1B1*15 overexpressing oocytes was decreased compared with that in SLCO1B1*15, but no change occurred with fluvastatin. The fold change of in vitro Clint for pitavastatin in SLCO1B1*15 compared to SLCO1B1*1a was larger than that of pravastatin (p<0.0001). The Cl/F of pitavastatin was decreased to a greater degree in subject with SLCO1B1*15/*15 compared to that of pravastatin in vivo (p<0.01), consistent with in vitro study. As a result, Cmax and AUC of these non-metabolized substrates were increased by SLCO1B1*15 variant. However, the greater decrease in the transport activity for pitavastatin in SLCO1B1*15 variant compared to SLCO1B1*1a was associated with the greater effect on the pharmacokinetics of pitavastatin compare to pravastatin in relation to the SLCO1B1 genetic polymorphism.
Conclusions The fold changes in major pharmacokinetic parameters of pitavastatin in subjects with OATP1B1*15/*15 compared to OATP1B1*1a/*1a were larger than those of pravastatin. Considering the lipophilicity and higher affinity to the OATP1B1 transporter of pitavastatin, physicochemical properties and in vitro transporter activity may contribute the different effect of OAPT1B1 polymorphism on the pharmacokinetics of pravastatin and pitavastatin, and it suggested that substrate dependency in the consequences of the SLCO1B1*15 variant could modulate the effect of SLCO1B1 polymorphism on the disposition of pitavastatin and pravastatin.
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