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 (k _uptake) was estimated to describe OATP function. Rifampicin decreased k _uptake (-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 k _uptake values (P < 0.05), with negligible impact on blood exposure (P < 0.05). In males, neither liver exposure, blood exposure, nor k _uptake were affected by aging (P < 0.05). k _uptake was positively and negatively correlated with liver (P < 0.01, R ² = 0.78) and blood (P < 0.01, R ² = 0.40) exposures respectively. The impact of OATP function (k _uptake) 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.