RESUMO
Fexofenadine is useful in various allergic disease treatment.However,the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking.This study aimed to verify the validity of previously proposed genetic factors through fexofenadine population pharmaco-kinetic modeling and to explore the quantitative correlations affecting the pharmacokinetic variability.Polymorphisms of the organic-anion-transporting-polypeptide(OATP)1B1 and 2B1 have been proposed to be closely related to fexofenadine pharmacokinetic diversity.Therefore,modeling was performed using fexofenadine oral exposure data according to the OATP1B1-and 2B1-polymorphisms.OATP1B1 and 2B1 were identified as effective covariates of clearance(CL/F)and distribution volume(V/F)-CL/F,respectively,in fexofenadine pharmacokinetic variability.CL/F and average steady-state plasma con-centration of fexofenadine differed by up to 2.17-and 2.20-folds,respectively,depending on the OATP1B1 polymorphism.Among the individuals with different OATP2B1 polymorphisms,the CL/F and V/F differed by up to 1.73-and 2.00-folds,respectively.Ratio of the areas under the curves following single-and multiple-administrations,and the cumulative ratio were significantly different between OATP1B1-and 2B1-polymorphism groups.Based on quantitative prediction comparison through a model-based approach,OATP1B1 was confirmed to be relatively more important than 2B1 regarding the degree of effect on fexofenadine pharmacokinetic variability.Based on the established pharmacokinetic-pharmacodynamic relationship,the difference in fexofenadine efficacy according to genetic poly-morphisms of OATP1B1 and 2B1 was 1.25-and 0.87-times,respectively,and genetic consideration of OATP1B1 was expected to be important in the pharmacodynamics area as well.This population phar-macometrics study will be a very useful starting point for fexofenadine precision medicine.
RESUMO
The study was designed to explore the drug-drug interactions mechanisms mediated by OATP1B1 between traditional Chinese medicine Danshensu and rosuvastatin. First, the changes of rosuvastatin pharmacokinetics were investigated in presence of Danshensu in rats. Then, the primary rat hepatocytes model was established to explore the effects of Danshensu on the uptake of rosuvastatin by hepatocytes. Finally, HEK293T cells with overexpression of OATP1B1*1a and OATP1B1*5 were established using a lentiviral delivery system to explore the effects of Danshensu on the uptake of rosuvastatin. Rosuvastatin pharmacokinetic parameters of Cmax, AUC0-t, AUC0-∞ were increased about 123%, 194% and 195%, by Danshensu in rats, while the CLz/F value was decreased by 60%. Uptake of rosuvastatin in the primary rat hepatocytes was decreased by 3.13%, 41.15% and 74.62%, respectively in the presence of 20, 40 and 80 μmol·L-1 Danshensu. The IC50 parameters was (53.04 ± 2.43) μmol·L-1. The inhibitory effect of Danshensu on OATP1B1 mediated transport of rosuvastatin was related to the OATP1B1 gene type. In OATP1B1*5-HEK293T mutant cells, transport of rosuvastatin were reduced by (39.11 ± 4.94) % and (63.61 ± 3.94) %, respectively, by Danshensu at 1 and 10 μmol·L-1. While transport of rosuvastatin was reduced by (8.22 ± 2.40) % and (11.56 ± 3.04) % and in OATP1B1*1a cells, respectively. Danshensu significantly altered the pharmacokinetics of rosuvastatin in rats, which was related to competitive inhibition of transport by OATP1B1. Danshensu exhibited a significant activity in the inhibition of rosuvastatin transport by OATP1B1*5-HEK293T, but not by OATP1B1*1a, suggesting a dependence on OATP1B1 sequence.
RESUMO
MicroRNAs (miRNAs) are a family of non-coding RNA that are able to adjust the expression of many proteins, including ATP-binding cassette transporter and organic cation transporter. We sought to evaluate the effect of miR-511 on the regulation of OATP1B1 expression by free fatty acids. When using free fatty acids to stimulate Chang liver cells, we found that the expression of miR-511 increased significantly while the expression of OATP1B1 decreased. We also proved that SLCO1B1 is the target gene of miR-511 with a bioinformatics analysis and using the dual luciferase reporter assay. Furthermore, the expressions of SLCO1B1 and OATP1B1 decreased if transfecting Chang liver cells with miR-511, but did not increase when transfecting the inhibitors of miR-511 into steatosis cells. Our study indicates that miR-511 may play an important role in the regulation of OATP1B1 expression by free fatty acids.
Assuntos
Humanos , Biologia Computacional , Ácidos Graxos não Esterificados , Fígado , Luciferases , MicroRNAs , RNA não TraduzidoRESUMO
Objective To study the relationship between the OATP1B1 521T ＞ C genetic polymorphism and essential hypertension.Methods 164 essential hypertension subjects and 159 normotensive subjects were detected by the TaqMan-MGB probe real-time fluorescence quantitative PCR,and the results were compared with those of DNA sequencing.Results The frequencies of T/C genotype and C allele of OATP1B1 521T ＞ C gene of the essential hypertension subjects were obviously lower than those of the normotensive subjects(T/C genotype:0.16 vs 0.25,P ＜0.05 ;C allele:0.10 vs 0.17,P ＜0.05),The difference was significant.Binary logistic stepwise regression analysis was used for evaluatine the risk factors of essential hypertension,there was significant relationship between OATP1 B1 52IT ＞ C gene polymorphism and essential hypertension.Conclusion The SLCO1 B1 521T ＞ C variant was common in Chinese essential hypertension population,but the difference of frequency of SLCO1B1 52IT ＞ Cmuton between the essential hypertension patients and the normotensive controls was of obviously statistical significance,which indicates that the SLCO1B1521T ＞ C variant maybe associate with essential hypertension.