Organic anion-transporting polypeptides(OATP)transporter function,which mediates many drugs'liver uptake,was investigated as a molecular determinant of pharmacokinetic variability.Whole-body PET imaging using 11C-...Organic anion-transporting polypeptides(OATP)transporter function,which mediates many drugs'liver uptake,was investigated as a molecular determinant of pharmacokinetic variability.Whole-body PET imaging using 11C-glyburide,a metabolically stable OATP probe,was performed in 16 healthy humans.Ten subjects underwent another 11C-glyburide PET acquisition after OATP inhibition using rifampicin.Subjects were sorted according to age and sex:males<30y(24.0±3.2 y,n=7),males>50y(57.5±5.6 y,n=4),and females>50y(60.6±2.4 y,n=5).The blood-to-liver transfer rate(kuptake)was estimated to describe OATP function.Rifampicin decreased kuptake(−73±13%,P<0.001)and liver exposure(−50±10%,P<0.001)while increasing exposure in blood(+24±24%,P<0.01),myocardium,spleen,and brain(P<0.05).No evidence of extra-hepatic rifampicin-inhibitable transport of 11C-glyburide was found.Baseline liver exposure was 42.6±18.4%higher(P<0.05)in females>50y compared with males>50 y,consistent with higher kuptake values(P<0.05),with negligible impact on blood exposure(P<0.05).In males,neither liver exposure,blood exposure,nor kuptake were affected by aging(P<0.05).kuptake was positively and negatively correlated with liver(P<0.01,R^(2)=0.78)and blood(P<0.01,R2=0.40)exposures respectively.The impact of OATP function(kuptake)on liver exposure was 4-fold more pronounced than on blood exposure.OATP function may thus drive important sex-related differences in liver exposure,which were not discernible through conventional blood-based pharmacokinetics.展开更多
基金funded by grant ANR-16-CE17-0011(France)and performed on a platform member of the France Life Imaging network(grant ANR-11-INBS-0006,France).
文摘Organic anion-transporting polypeptides(OATP)transporter function,which mediates many drugs'liver uptake,was investigated as a molecular determinant of pharmacokinetic variability.Whole-body PET imaging using 11C-glyburide,a metabolically stable OATP probe,was performed in 16 healthy humans.Ten subjects underwent another 11C-glyburide PET acquisition after OATP inhibition using rifampicin.Subjects were sorted according to age and sex:males<30y(24.0±3.2 y,n=7),males>50y(57.5±5.6 y,n=4),and females>50y(60.6±2.4 y,n=5).The blood-to-liver transfer rate(kuptake)was estimated to describe OATP function.Rifampicin decreased kuptake(−73±13%,P<0.001)and liver exposure(−50±10%,P<0.001)while increasing exposure in blood(+24±24%,P<0.01),myocardium,spleen,and brain(P<0.05).No evidence of extra-hepatic rifampicin-inhibitable transport of 11C-glyburide was found.Baseline liver exposure was 42.6±18.4%higher(P<0.05)in females>50y compared with males>50 y,consistent with higher kuptake values(P<0.05),with negligible impact on blood exposure(P<0.05).In males,neither liver exposure,blood exposure,nor kuptake were affected by aging(P<0.05).kuptake was positively and negatively correlated with liver(P<0.01,R^(2)=0.78)and blood(P<0.01,R2=0.40)exposures respectively.The impact of OATP function(kuptake)on liver exposure was 4-fold more pronounced than on blood exposure.OATP function may thus drive important sex-related differences in liver exposure,which were not discernible through conventional blood-based pharmacokinetics.
