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Rheumatoid arthritis downregulates the drug transporter OATP1B1: Fluvastatin as a probe.
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2020-02-11 , DOI: 10.1016/j.ejps.2020.105264 Juciene Aparecida Caris 1 , Jhohann Richard de Lima Benzi 1 , Flávio Falcão Lima de Souza 2 , Renê Donizeti Ribeiro de Oliveira 2 , Eduardo Antônio Donadi 2 , Vera Lucia Lanchote 1
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2020-02-11 , DOI: 10.1016/j.ejps.2020.105264 Juciene Aparecida Caris 1 , Jhohann Richard de Lima Benzi 1 , Flávio Falcão Lima de Souza 2 , Renê Donizeti Ribeiro de Oliveira 2 , Eduardo Antônio Donadi 2 , Vera Lucia Lanchote 1
Affiliation
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AIMS
Rheumatoid arthritis (RA) is a long term autoimmune inflammatory disease characterized by high autoantibody production and cytokine release, especially IL-6 and TNF-α. Some clinical studies have shown the effect of RA on CYP metabolism. However, the effect of RA on the drug transporter OATP1B1 remains a gap.
METHODS
Patients with RA under pharmacological treatment (n = 10) and healthy volunteers (n = 15) treated for seven consecutive days with racemic fluvastatin (20, 40, or 80 mg/24 h) were investigated. Serial blood samples were collected during the last dose interval. All participants were assessed for cytokine profile and CYP2C9 genotype.
RESULTS
Patients with RA showed increased plasma concentrations of IFN-γ and TNF-α up to two and four times, respectively, when compared to healthy volunteers, whereas CYP2C9 activity based on genotype was considered normal or slightly reduced for both investigated groups. When compared to healthy volunteers, patients with RA presented higher values (median and 25th-75th percentiles) of normalized AUC for 20 mg dose (250 [114-405] vs. 96.7 [78.1-131] ng h mL-1 for (-)-3S,5R-fluvastatin and 163 [96.9-325] vs. 83.1 [61.7-107] ng⋅h⋅mL-1 for (+)-3R,5S-fluvastatin) and lower values of CL/F (40.9 [24.5-89.1] vs. 103 [75.9-128] L⋅h-1 for (-)-3S,5R-fluvastatin and 61.4 [30.6-103] vs. 120 [93.0-162] L⋅h-1 for (+)-3R,5S-fluvastatin) and V/F (73.0 [28.5-117] vs. 143 [108-221] L for (-)-3S,5R-fluvastatin and 93.9 [32.7-116] vs. 153 [122-234] L for (+)-3R,5S-fluvastatin) for both enantiomers.
CONCLUSION
The lower values of CL/F and V/F for both fluvastatin enantiomers in RA patients suggest that the inflammatory disease downregulates the sinusoidal drug transporter OATP1B1, the rate-determining step in the hepatic clearance of fluvastatin.
中文翻译：
类风湿关节炎下调药物转运蛋白OATP1B1：氟伐他汀作为探针。
AIMS类风湿关节炎（RA）是一种长期的自身免疫性炎症性疾病，其特征在于自身抗体的产生高和细胞因子的释放，尤其是IL-6和TNF-α。一些临床研究表明RA对CYP代谢的影响。但是，RA对药物转运蛋白OATP1B1的影响仍然存在差距。方法对连续7天接受外消旋氟伐他汀（20、40或80 mg / 24 h）药物治疗的RA患者（n = 10）和健康志愿者（n = 15）进行调查。在最后的剂量间隔期间收集系列血样。评估所有参与者的细胞因子谱和CYP2C9基因型。结果与健康志愿者相比，RA患者的血浆IFN-γ和TNF-α浓度分别升高了两倍和四倍，CYP2C9活性基于基因型被认为是正常的或两个研究组略有减少。与健康志愿者相比，RA患者在20 mg剂量（250 [114-405]与96.7 [78.1-131] ng h mL-1）的（-时）表现出更高的标准化AUC值（中位数和25-75％） ）-3S，5R-氟伐他汀和163 [96.9-325]与83.1 [61.7-107] ng·h·mL-1（（+）-3R，5S-氟伐他汀）和较低的CL / F值（40.9 [ （-）-3S，5R-氟伐他汀的L⋅h-1分别为24.5-89.1]和103 [75.9-128]L⋅h-1和（+）的61.4 [30.6-103] vs. 120 [93.0-162]L⋅h-1 ）-3R，5S-氟伐他汀）和V / F（-）-3S，5R-氟伐他汀和93.9 [32.7-116]与153 [122] L分别为73.0 [28.5-117]与143 [108-221] L -234] L表示两种对映体的（+）-3R，5S-氟伐他汀）。
更新日期：2020-02-12
中文翻译：
类风湿关节炎下调药物转运蛋白OATP1B1：氟伐他汀作为探针。
AIMS类风湿关节炎（RA）是一种长期的自身免疫性炎症性疾病，其特征在于自身抗体的产生高和细胞因子的释放，尤其是IL-6和TNF-α。一些临床研究表明RA对CYP代谢的影响。但是，RA对药物转运蛋白OATP1B1的影响仍然存在差距。方法对连续7天接受外消旋氟伐他汀（20、40或80 mg / 24 h）药物治疗的RA患者（n = 10）和健康志愿者（n = 15）进行调查。在最后的剂量间隔期间收集系列血样。评估所有参与者的细胞因子谱和CYP2C9基因型。结果与健康志愿者相比，RA患者的血浆IFN-γ和TNF-α浓度分别升高了两倍和四倍，CYP2C9活性基于基因型被认为是正常的或两个研究组略有减少。与健康志愿者相比，RA患者在20 mg剂量（250 [114-405]与96.7 [78.1-131] ng h mL-1）的（-时）表现出更高的标准化AUC值（中位数和25-75％） ）-3S，5R-氟伐他汀和163 [96.9-325]与83.1 [61.7-107] ng·h·mL-1（（+）-3R，5S-氟伐他汀）和较低的CL / F值（40.9 [ （-）-3S，5R-氟伐他汀的L⋅h-1分别为24.5-89.1]和103 [75.9-128]L⋅h-1和（+）的61.4 [30.6-103] vs. 120 [93.0-162]L⋅h-1 ）-3R，5S-氟伐他汀）和V / F（-）-3S，5R-氟伐他汀和93.9 [32.7-116]与153 [122] L分别为73.0 [28.5-117]与143 [108-221] L -234] L表示两种对映体的（+）-3R，5S-氟伐他汀）。
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