Imaging SLCO Transport function in clearance and non-clearance Organs in Human: implication for drug PharmacoKinetics and tissue disposition variability – ISOTOPK
In Human, the fate of drugs in the body is estimated thanks to clinical pharmacokinetics (PK) through the determination of its concentrations in plasma. Clinically relevant gender and age-related differences in drug PK have been described, although the molecular determinants for such a variability remain misunderstood and cannot be solely explained by the intrinsic activity of metabolic enzymes. However, in view of drug efficacy or toxicity, it is the target tissue concentration rather than the plasma concentration that is the most relevant.
It is often hypothesized that passive diffusion is the main transport mechanism allowing for drug exposure to organs. The identification of membrane transporter in many non-clearance organs suggests that penetration of drugs in tissues may be controlled by active carrier-mediated processes with limited impact on measurable plasma PK. The SLCO transporter (SoLute Carrier O) family was shown to mediate the hepatic uptake of many drugs. Interestingly, SLCO expression was also detected in non-clearance organs including human heart, blood-brain barrier, epithelial lung cells, ovary, mammary duct and muscles, suggesting a functional role for SLCO in controlling the access of drugs to target and/or vulnerable tissues.
The main objective of the IsotoPK project is to unveil and quantify for the first time in vivo in Human the contribution of SLCO transporters on drug exposure to clearance and non-clearance organs and challenge the assumption that only passive diffusion leads to tissue exposure. The secondary objective of the project is to investigate hepatic and extrahepatic SLCO function as a variability factor for drug disposition, PK and metabolism according to drug-drug interaction with SLCO inhibitors, normal ageing and gender.
IsotoPK is a clinical PK study (Phase I) that will be performed in healthy volunteers. We recently developed 11C-glyburide, a Positron Emission Tomography (PET) imaging probe dedicated to SCLO function imaging. 11C-glyburide is a substrate of hepatic and extrahepatic SLCO isoforms. The tissue kinetics of 11C-glyburide will be measured using an innovative simultaneous PET-MR (magnetic resonance) imaging system allowing for low radiation dose whole-body dynamic (4D) acquisitions and direct delineation of the organs. PK analysis of the imaging data regarding 11C-glyburide arterial plasma kinetics will allow for the accurate estimation of the parameters that describe the exchange between blood and the investigated organs. These parameters will be compared before and after a single dose rifampicin, a potent SLCO inhibitor. 11C-glyburide PET-MR scans will be performed in senior males and females (10 individuals in each group, age 50-70 y.o) to unveil SLCO-mediated uptake in gender specific organs (gonads, mammary glands, prostate, etc) and to determine whether the hepatic and extrahepatic SLCO function can be identified as a new PK factor of variability between males and females in the older population with an increased risk of drug induced iatrogenesis. Data will be compared to those obtained in a younger population (male 18-30 y.o) to address the influence of normal ageing on SLCO function.
The IsotoPK project is proposed by a young and multidisciplinary research team. We expect the present study to show for the first time in human that SLCO-mediated uptake controls drug accumulation in several organs. We will assess the correlation between SLCO function in the liver, plasma disposition and metabolism, showing the interplay or possible functional compensation between SLCO function and metabolic enzyme activity in vivo. The overall aim of the project is to unveil a specific biological mechanism at the tissue level in Human and predict its potential involvement in PK variability due to gender and normal ageing. The results may influence the regulatory guidelines for drug development, taking into account the tissue, age or gender-related specificities in SLCO function.
Monsieur Nicolas Tournier (Commisariat à l'énergie atomique et aux énergies alternatives)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CEA/DRF/SHFJ/IMIV Commisariat à l'énergie atomique et aux énergies alternatives
Help of the ANR 278,518 euros
Beginning and duration of the scientific project: November 2016 - 36 Months