Imaging the impact of sex and age on OATP function in humans: Consequences for whole-body pharmacokinetics and liver exposure

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 11 C-glyburide, a metabolically stable OATP probe, was performed in 16 healthy humans. Ten subjects underwent another 11 C-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 11 C-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. Organic anion-transporting polypeptides (OATP) function, which mediates the uptake transport of many drugs by hepatocytes, is higher in females, resulting in greater liver exposure. This sex difference was not discernible through blood-based pharmacokinetics.