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

Abstract

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 [ 18 F]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. [ 18 F]Atorvastatin was synthesized via a previously optimized 18 F-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 [ 18 F]atorvastatin in all tissues compared with the primary target organ (liver), excretory pathways (kidneys and small intestine), and stomach. Uptake of [ 18 F]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 [ 18 F]atorvastatin kinetics in the liver. A strong correlation (R 2 > 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 [ 18 F]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 [ 18 F]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 [ 18 F]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.

CNS Drug Delivery in Stroke: Improving Therapeutic Translation From the Bench to the Bedside

“…111,112 Transporters influence the pharmacokinetic properties of commonly prescribed drugs, leading to variable exposure of brain tissue. [113][114][115] In assessing CNS drug penetration, a common misconception is that drug presence in cerebrospinal fluid (CSF) is a surrogate for drug levels in brain tissue. As elegantly outlined by Pardridge, 116 a CSF concentration can only be interpreted to reflect drug penetration across the blood-CSF barrier.…”

Sex-based differences in nuclear medicine imaging and therapy

“…From preclinical data, we know that sex difference influences the finding on PET imaging. For example, preclinical PET studies with [ 18 F]atorvastatin demonstrated faster and higher hepatic uptake and clearance in female compared to male rats, probably due to higher efficiency for exchange between arterial blood and hepatic tissue [1] (Fig. 1).…”

Hydrogel and nanoparticle carriers for kidney disease therapy: trends and recent advancements

“…For example, atorvastatin has demonstrated antioxidant, anti-inflammatory, and anti-apoptotic activities that render it a protective drug against renal injury. However, the pharmacokinetics and biodistribution of atorvastatin in healthy female and male rats indicated that it exhibited an elevated accumulation within the liver (approximately 20-fold the amount in the kidneys), indicative of increased dosage required to achieve renal therapeutic effect [19]. Furthermore, severe liver injury was developed in diabetic rats receiving 20 mg kg −1 atorvastatin, as manifested by diminished liver enzyme activity, elevated bilirubin levels, changes in liver tissue architecture, hepatocyte necrosis, lymphocytic infiltration, and fibrosis.…”