[18F]Atorvastatin Pharmacokinetics and Biodistribution in Healthy Female and Male Rats

• Published in: Molecular pharmaceutics Vol. 18; no. 9; pp. 3378 - 3386
• Main Authors: Clemente, Gonçalo S, Antunes, Inês F, Sijbesma, Jürgen W. A, van Waarde, Aren, Lammertsma, Adriaan A, Dömling, Alexander, Elsinga, Philip H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.09.2021
• Subjects: Animals; Atorvastatin - administration & dosage; Atorvastatin - analysis; Atorvastatin - chemistry; Atorvastatin - pharmacokinetics; Female; Fluorine Radioisotopes - administration & dosage; Fluorine Radioisotopes - analysis; Hepatobiliary Elimination; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - analysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Male; Molecular Imaging - methods; Positron-Emission Tomography - methods; Radiopharmaceuticals - administration & dosage; Radiopharmaceuticals - analysis; Rats; Rats, Wistar; Sex Factors; Tissue Distribution; pharmacokinetics; fluorine-18; positron emission tomography (PET); atorvastatin; sexual dimorphism
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.1c00305

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic mechanisms have been associated with statins, particularly with atorvastatin. Therefore, the assessment of [18F]­atorvastatin kinetics with positron emission tomography (PET) may elucidate the mechanism of action of statins and the impact of sexual dimorphism, which is one of the most debated interindividual variations influencing the therapeutic efficacy. [18F]­Atorvastatin was synthesized via a previously optimized 18F-deoxyfluorination strategy, used for preclinical PET studies in female and male Wistar rats (n = 7 for both groups), and for subsequent ex vivo biodistribution assessment. PET data were fitted to several pharmacokinetic models, which allowed for estimating relevant kinetic parameters. Both PET imaging and biodistribution studies showed negligible uptake of [18F]­atorvastatin in all tissues compared with the primary target organ (liver), excretory pathways (kidneys and small intestine), and stomach. Uptake of [18F]­atorvastatin was 38 ± 3% higher in the female liver than in the male liver. The irreversible 2-tissue compartment model showed the best fit to describe [18F]­atorvastatin kinetics in the liver. A strong correlation (R2 > 0.93) between quantitative K i (the radiotracer’s unidirectional net rate of influx between compartments) and semi-quantitative liver’s SUV (standard uptake value), measured between 40 to 90 min, showed potential to use the latter parameter, which circumvents the need for blood sampling as a surrogate of K i for monitoring [18F]­atorvastatin uptake. Preclinical assays showed faster uptake and clearance for female rats compared to males, seemingly related to a higher efficiency for exchanges between the arterial input and the hepatic tissue. Due to the slow [18F]­atorvastatin kinetics, equilibrium between the liver and plasma concentration was not reached during the time frame studied, making it difficult to obtain sufficient and accurate kinetic information to quantitatively characterize the radiotracer pharmacokinetics over time. Nevertheless, the reported results suggest that the SUV can potentially be used as a simplified measure, provided all scans are performed at the same time point. Preclinical PET-studies with [18F]­atorvastatin showed faster uptake and clearance in female compared to male rats, apparently related to higher efficiency for exchange between arterial blood and hepatic tissue.