Objective To analyze the relationship between genetic polymorphisms of organic anion transporting polypeptide ( SLCO1B1 and SLCO1B3) and mycophenolic acid ( MPA) pharmacokinetics in Chinese kidney transplant recipient...Objective To analyze the relationship between genetic polymorphisms of organic anion transporting polypeptide ( SLCO1B1 and SLCO1B3) and mycophenolic acid ( MPA) pharmacokinetics in Chinese kidney transplant recipients. Methods Gene mutations ( SLCO1B3 T334G,SLCO1B1 A338G) were detected in 68 recipi-展开更多
本试验旨在测定和比较5个绿壳蛋鸡群体中EAV-HP在溶质载体有机阴离子转运蛋白家族成员1B3（solute carrier organic anion transporter family member 1B3,SLCO1B3）基因的5′-非编码区插入整合的频率和类型。所选5个绿壳蛋鸡群体包括3...本试验旨在测定和比较5个绿壳蛋鸡群体中EAV-HP在溶质载体有机阴离子转运蛋白家族成员1B3（solute carrier organic anion transporter family member 1B3,SLCO1B3）基因的5′-非编码区插入整合的频率和类型。所选5个绿壳蛋鸡群体包括3个北京地区的商业群体（北京-LK、北京-LF和北京-YM）、贵州长顺绿壳蛋鸡群体和四川省地方品种旧院黑鸡;采用双重PCR对EAV-HP的插入整合进行检测,并利用DNA测序的方法判断EAV-HP的主要突变位点。结果表明,5个绿壳蛋鸡群体均拥有一定数量的EAV-HP插入整合的个体,表现为杂合（LC/N）和纯合（LC/LC）基因型,均可产绿壳蛋,其中旧院黑鸡的绿壳蛋频率最低,仅为28.90%,其次是北京-LF群体,为46.94%,其他3个群体的绿壳蛋频率为83.33%~84.62%;经卡方检验,北京-LF和旧院黑鸡群体符合Hardy-Weinberg平衡（P〉0.05）,而其他3个群体则极显著偏离Hardy-Weinberg平衡状态（P〈0.01）。DNA测序结果显示这5个绿壳蛋鸡群体中EAV-HP插入整合的序列与之前报道的东乡绿壳蛋鸡的KC632577.1完全一致。地方品种旧院黑鸡的绿壳蛋频率较低,建议利用双重PCR检测的分子标记辅助选择方法加以提高。展开更多
The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics.In addition,we compared the fluvastatin pharmacokinetics differences between extended-release(ER)8...The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics.In addition,we compared the fluvastatin pharmacokinetics differences between extended-release(ER)80 mg tablet and immediate-release(IR)40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms.In this open-label,randomized,two-period,two-treatment,crossover study(n=24),effects of ABCG2,SLCO1B1,ABCB1,CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed.The administration dosage for IR 40 mg and ER 80 mg were twice and once daily,respectively,for total 7 d.Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d.The lower exposure following ER was observed.For ER tablets,SLCO1B1 T521C genotype correlated with AUC 0-24 of repeat doses(P=0.010).SLCO1B1 T521C genotype had no statistically significant effect on AUC 0-24 of IR capsule of fluvastatin after single or repeated doses.In vitro study demonstrated that when the concentration of fluvastatin was low(<1μmol/l),the uptake of fluvastatin in the HEK293-OATP1B1 with SLCO1B1521TT(K m=0.18μmol/l)was faster than that with SLCO1B1521CC(K m=0.49μmol/l),On the other hand,when concentration reached to higher level(>1μmol/l),transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1521TT(K m=11.4μmol/l)and with SLCO1B1521TCC(K m=15.1μmol/l)tend to be the same.It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations.We recommend that formulation should be incorporated into future pharmacogenomics studies.展开更多
Rifampin, a member of the rifamycin class of antibiotics, is well known for its ability to activate the pregnant X receptor and induce drug-metabolizing enzymes and transporters. Available data suggest rifampin entry ...Rifampin, a member of the rifamycin class of antibiotics, is well known for its ability to activate the pregnant X receptor and induce drug-metabolizing enzymes and transporters. Available data suggest rifampin entry into hepatocytes is mediated by OATP1B1. Accordingly, it is therefore plausible that modulation of the intracellular concentration of rifampin by OATP1B1 genetic polymorphisms would influence the degree of CYP3A induction. AIM: To study the association between haplotypes of the SLCO1B1 and the rifampicin-mediated inducible CYP3A4 activity. A single-point determination of midazolam plasma concentration method was developed to assess the constitutive and inducible CYP3A4 activity. A pharmacokinetic study of a single dose of 450 mg rifampicin was conducted to evaluate the mechanism of rifampicin-midazolam interaction in different SLCO1B1 genotypic subjects. METHODS: Twenty-three healthy volunteers with different SLCO1B1 haplotypes (7 for SLCO1B1*1a/*1a, 7 for SLCO1B1*1b/*1b, 7 for SLCO1B1*1b/*15 and 2 for SLCO1B1*15/*15) were enrolled in this study. Each was given a single oral dose of 7.5 mg midazolam on day 0 and day 6. Rifampicin of 450 mg was given from day 1 to day 5. Plasma concentrations of midazolam were measured for up to 8 hours by LC-MS, and its pharmacokinetic parameters were analyzed. Plasma concentrations of a single oral dose of 450 mg rifampicin were measured for up to 12 hours. RESULTS: A significant correlation (r2=0.763, P<0.001, n=23) was found between AUC(0-∞) and the single plasma concentration of midazolam at 2.5 hour (C2.5 h). The 2.5 h midazolam measurement was an optimal predictor of CYP3A phenotype. However, the percentage reduction of AUC(0-∞) or C2.5 h in different SLCO1B1 haplotypes was not significantly different. The pharmacokinetics parameters of rifampin were not significantly different between the 521T>C mutant group and the control group. CONCLUSION: A single blood concentration at 2.5 h after 7.5 mg oral midazolam intake can be used to predict CYP3A activity. The SLCO1B1 haplotypes do not influence the extent of inducible CYP3A activity by rifampin. SLCO1B1 genotypes has no significant impact on the disposition of rifampin in vivo.展开更多
文摘Objective To analyze the relationship between genetic polymorphisms of organic anion transporting polypeptide ( SLCO1B1 and SLCO1B3) and mycophenolic acid ( MPA) pharmacokinetics in Chinese kidney transplant recipients. Methods Gene mutations ( SLCO1B3 T334G,SLCO1B1 A338G) were detected in 68 recipi-
文摘本试验旨在测定和比较5个绿壳蛋鸡群体中EAV-HP在溶质载体有机阴离子转运蛋白家族成员1B3（solute carrier organic anion transporter family member 1B3,SLCO1B3）基因的5′-非编码区插入整合的频率和类型。所选5个绿壳蛋鸡群体包括3个北京地区的商业群体（北京-LK、北京-LF和北京-YM）、贵州长顺绿壳蛋鸡群体和四川省地方品种旧院黑鸡;采用双重PCR对EAV-HP的插入整合进行检测,并利用DNA测序的方法判断EAV-HP的主要突变位点。结果表明,5个绿壳蛋鸡群体均拥有一定数量的EAV-HP插入整合的个体,表现为杂合（LC/N）和纯合（LC/LC）基因型,均可产绿壳蛋,其中旧院黑鸡的绿壳蛋频率最低,仅为28.90%,其次是北京-LF群体,为46.94%,其他3个群体的绿壳蛋频率为83.33%~84.62%;经卡方检验,北京-LF和旧院黑鸡群体符合Hardy-Weinberg平衡（P〉0.05）,而其他3个群体则极显著偏离Hardy-Weinberg平衡状态（P〈0.01）。DNA测序结果显示这5个绿壳蛋鸡群体中EAV-HP插入整合的序列与之前报道的东乡绿壳蛋鸡的KC632577.1完全一致。地方品种旧院黑鸡的绿壳蛋频率较低,建议利用双重PCR检测的分子标记辅助选择方法加以提高。
基金This study was supported by grants from the National Key R&D Program of China(No.2016YFC0904900)National Natural Science Foundation(No.81673509 and No.81573504)of China+1 种基金Natural Science Foundation of Beijing Municipality(No.7171012)National Science and Technology Major Projects for“Major New Drugs Innovation and Development”of China(No.2017ZX09304028 and No.2017ZX09101001).
文摘The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics.In addition,we compared the fluvastatin pharmacokinetics differences between extended-release(ER)80 mg tablet and immediate-release(IR)40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms.In this open-label,randomized,two-period,two-treatment,crossover study(n=24),effects of ABCG2,SLCO1B1,ABCB1,CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed.The administration dosage for IR 40 mg and ER 80 mg were twice and once daily,respectively,for total 7 d.Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d.The lower exposure following ER was observed.For ER tablets,SLCO1B1 T521C genotype correlated with AUC 0-24 of repeat doses(P=0.010).SLCO1B1 T521C genotype had no statistically significant effect on AUC 0-24 of IR capsule of fluvastatin after single or repeated doses.In vitro study demonstrated that when the concentration of fluvastatin was low(<1μmol/l),the uptake of fluvastatin in the HEK293-OATP1B1 with SLCO1B1521TT(K m=0.18μmol/l)was faster than that with SLCO1B1521CC(K m=0.49μmol/l),On the other hand,when concentration reached to higher level(>1μmol/l),transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1521TT(K m=11.4μmol/l)and with SLCO1B1521TCC(K m=15.1μmol/l)tend to be the same.It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations.We recommend that formulation should be incorporated into future pharmacogenomics studies.
文摘Rifampin, a member of the rifamycin class of antibiotics, is well known for its ability to activate the pregnant X receptor and induce drug-metabolizing enzymes and transporters. Available data suggest rifampin entry into hepatocytes is mediated by OATP1B1. Accordingly, it is therefore plausible that modulation of the intracellular concentration of rifampin by OATP1B1 genetic polymorphisms would influence the degree of CYP3A induction. AIM: To study the association between haplotypes of the SLCO1B1 and the rifampicin-mediated inducible CYP3A4 activity. A single-point determination of midazolam plasma concentration method was developed to assess the constitutive and inducible CYP3A4 activity. A pharmacokinetic study of a single dose of 450 mg rifampicin was conducted to evaluate the mechanism of rifampicin-midazolam interaction in different SLCO1B1 genotypic subjects. METHODS: Twenty-three healthy volunteers with different SLCO1B1 haplotypes (7 for SLCO1B1*1a/*1a, 7 for SLCO1B1*1b/*1b, 7 for SLCO1B1*1b/*15 and 2 for SLCO1B1*15/*15) were enrolled in this study. Each was given a single oral dose of 7.5 mg midazolam on day 0 and day 6. Rifampicin of 450 mg was given from day 1 to day 5. Plasma concentrations of midazolam were measured for up to 8 hours by LC-MS, and its pharmacokinetic parameters were analyzed. Plasma concentrations of a single oral dose of 450 mg rifampicin were measured for up to 12 hours. RESULTS: A significant correlation (r2=0.763, P<0.001, n=23) was found between AUC(0-∞) and the single plasma concentration of midazolam at 2.5 hour (C2.5 h). The 2.5 h midazolam measurement was an optimal predictor of CYP3A phenotype. However, the percentage reduction of AUC(0-∞) or C2.5 h in different SLCO1B1 haplotypes was not significantly different. The pharmacokinetics parameters of rifampin were not significantly different between the 521T>C mutant group and the control group. CONCLUSION: A single blood concentration at 2.5 h after 7.5 mg oral midazolam intake can be used to predict CYP3A activity. The SLCO1B1 haplotypes do not influence the extent of inducible CYP3A activity by rifampin. SLCO1B1 genotypes has no significant impact on the disposition of rifampin in vivo.
