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

Abstract

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: males50y (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 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.

Keywords

• Liver exposure
• Imaging
• Drug transporter
• Drug–drug interaction
• Drug-induced liver injury
• Pharmacokinetics