In vivo evidence of functional OATP2B1 activity in human skeletal muscle using [11C]erlotinib PET

• In vivo measurement of OATP2B1 activity in human skeletal muscle • Use of [ 11 C]erlotinib as an OATP2B1-specific PET probe substrate • Oral erlotinib pre-treatment partially saturates muscular OATP2B1 transport • Findings suggest a role of OATP2B1 in muscle accumulation and toxicity of substrate drugs (e.g., statins) Organic anion-transporting polypeptide 2B1 (OATP2B1/SLCO2B1) is an uptake transporter expressed in the liver and in several extrahepatic tissues, including skeletal muscle. Muscular OATP2B1 is thought to facilitate intracellular accumulation of statins, potentially contributing to statin-induced myotoxicity. To investigate functional OATP2B1 activity in vivo in human skeletal muscle, we performed positron emission tomography (PET) with the radiolabelled OATP2B1 substrate [ 11 C]erlotinib. Nine healthy male volunteers (age: 31 ± 9 years) underwent two dynamic 60-min PET scans of the head with concurrent arterial blood sampling following intravenous injection of a microdose of [ 11 C]erlotinib (< 10 µg). The first scan was performed without any pharmacological pre-treatment (baseline scan), whereas the second scan was performed after pre-treatment with a single oral dose of unlabelled erlotinib (650 mg), administered 3.0 ± 0.1 h before the start of the PET scan. Volumes of interest (VOIs) were manually delineated for the right and left temporal muscle surrounding the skull on co-registered PET/magnetic resonance imaging (MRI) data and averaged to generate a global temporal muscle VOI. Time-activity curves for temporal muscle and arterial plasma were analysed using a 1-tissue-2-rate constant (1T2K) compartment model and Logan graphical analysis to estimate the total volume of distribution ( V T ) of [ 11 C]erlotinib (reflecting the steady-state muscle-to-plasma concentration ratio), as well as the rate constants for transfer of [ 11 C]erlotinib from plasma to muscle ( K 1 ) and from muscle to plasma ( k 2 ). Both Logan analysis and the 1T2K model demonstrated a significant reduction in V T after erlotinib pre-treatment compared with baseline ( V T Logan : baseline: 0.85 ± 0.11 mL/cm 3 , erlotinib: 0.70 ± 0.08 mL/cm 3 , −18 ± 8%, p = 0.00047; V T 1T2K : baseline: 0.83 ± 0.11 mL/cm 3 , erlotinib: 0.67 ± 0.07 mL/cm 3 , −18 ± 7%, p = 0.00033). K 1 showed a trend toward reduction after erlotinib pre-treatment without reaching statistical significance, whereas k 2 remained unchanged. Our findings demonstrate saturable distribution of [¹¹C]erlotinib to human skeletal muscle, consistent with functional OATP2B1 activity. These results support a mechanistic role for muscular OATP2B1 in statin-induced myotoxicity and highlight its potential broader relevance for the safety and pharmacology of other OATP2B1 substrate drugs.