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. 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, R2=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.