Imaging the impact of sex and age on OATP function in humans: Consequences for whole-body pharmacokinetics and liver exposure.
10.1016/j.apsb.2025.03.030
- Author:
Solène MARIE
1
;
Anne-Lise LECOQ
2
;
Louise BREUIL
1
;
Fabien CAILLÉ
1
;
Vincent LEBON
1
;
Claude COMTAT
1
;
Sébastien GOUTAL
1
;
Laurent BECQUEMONT
2
;
Michel BOTTLAENDER
1
;
Céline VERSTUYFT
3
;
Nicolas TOURNIER
1
Author Information
1. Université Paris-Saclay, CEA, Inserm, CNRS, BioMaps, Service Hospitalier Frédéric Joliot, Orsay 91401, France.
2. AP-HP. Université Paris-Saclay, Hôpital Bicêtre, Centre de Recherche Clinique, Le Kremlin Bicêtre 94270, France.
3. CESP, MOODS Team, INSERM UMR 1018, Faculté de Médecine, Univ Paris-Saclay, Le Kremlin Bicêtre F-94275, France.
- Publication Type:Journal Article
- Keywords:
Drug transporter;
Drug-induced liver injury;
Drug–drug interaction;
Gender;
Imaging;
Liver exposure;
Pharmacokinetics;
Solute carrier
- From:
Acta Pharmaceutica Sinica B
2025;15(5):2736-2745
- CountryChina
- Language:English
-
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: 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.
