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[18F]Atorvastatin Pharmacokinetics and Biodistribution in Healthy Female and Male Rats
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-08-05 , DOI: 10.1021/acs.molpharmaceut.1c00305 Gonçalo S Clemente 1 , Inês F Antunes 1 , Jürgen W A Sijbesma 1 , Aren van Waarde 1 , Adriaan A Lammertsma 1 , Alexander Dömling 2 , Philip H Elsinga 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-08-05 , DOI: 10.1021/acs.molpharmaceut.1c00305 Gonçalo S Clemente 1 , Inês F Antunes 1 , Jürgen W A Sijbesma 1 , Aren van Waarde 1 , Adriaan A Lammertsma 1 , Alexander Dömling 2 , Philip H Elsinga 1
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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 Ki (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 Ki 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.
中文翻译：
[18F]阿托伐他汀在健康雌性和雄性大鼠中的药代动力学和生物分布
他汀类药物是 3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂，广泛用于预防心血管疾病。然而，一系列多效机制与他汀类药物，特别是阿托伐他汀相关。因此，用正电子发射断层扫描（PET）评估[ 18 F]阿托伐他汀动力学可以阐明他汀类药物的作用机制和性别二态性的影响，这是影响治疗效果的最具争议的个体间差异之一。 [ 18 F]阿托伐他汀通过先前优化的18 F-脱氧氟化策略合成，用于雌性和雄性 Wistar 大鼠（两组n = 7）的临床前 PET 研究，以及随后的离体生物分布评估。 PET 数据适合多个药代动力学模型，从而可以估计相关的动力学参数。 PET 成像和生物分布研究均显示，与主要靶器官（肝脏）、排泄途径（肾脏和小肠）和胃相比，[ 18 F]阿托伐他汀在所有组织中的摄取量可以忽略不计。女性肝脏对[ 18 F]阿托伐他汀的摄取比男性肝脏高 38 ± 3%。不可逆的2组织室模型最适合描述肝脏中的[ 18 F]阿托伐他汀动力学。强相关性 (R 2 > 0.93) 在 40 至 90 分钟之间测量的定量K （放射性示踪剂在室之间的单向净流入率）和半定量肝脏 SUV（标准摄取值）之间的比较显示出使用后一个参数的潜力，从而避免了血液采样的需要作为K的替代物，用于监测 [ 18 F]阿托伐他汀的摄取。临床前试验显示，与雄性大鼠相比，雌性大鼠的摄取和清除速度更快，这似乎与动脉输入和肝组织之间的交换效率更高有关。由于[ 18 F]阿托伐他汀动力学缓慢，在研究的时间范围内肝脏和血浆浓度之间未达到平衡，因此难以获得足够且准确的动力学信息来定量表征放射性示踪剂随时间的药代动力学。尽管如此，报告的结果表明，只要所有扫描都在同一时间点进行，SUV 就有可能用作一种简化的措施。 [ 18 F]阿托伐他汀的临床前研究显示，与雄性大鼠相比，雌性大鼠的摄取和清除速度更快，这显然与动脉血和肝组织之间更高的交换效率有关。
更新日期：2021-09-06
中文翻译：
[18F]阿托伐他汀在健康雌性和雄性大鼠中的药代动力学和生物分布
他汀类药物是 3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂，广泛用于预防心血管疾病。然而，一系列多效机制与他汀类药物，特别是阿托伐他汀相关。因此，用正电子发射断层扫描（PET）评估[ 18 F]阿托伐他汀动力学可以阐明他汀类药物的作用机制和性别二态性的影响，这是影响治疗效果的最具争议的个体间差异之一。 [ 18 F]阿托伐他汀通过先前优化的18 F-脱氧氟化策略合成，用于雌性和雄性 Wistar 大鼠（两组n = 7）的临床前 PET 研究，以及随后的离体生物分布评估。 PET 数据适合多个药代动力学模型，从而可以估计相关的动力学参数。 PET 成像和生物分布研究均显示，与主要靶器官（肝脏）、排泄途径（肾脏和小肠）和胃相比，[ 18 F]阿托伐他汀在所有组织中的摄取量可以忽略不计。女性肝脏对[ 18 F]阿托伐他汀的摄取比男性肝脏高 38 ± 3%。不可逆的2组织室模型最适合描述肝脏中的[ 18 F]阿托伐他汀动力学。强相关性 (R 2 > 0.93) 在 40 至 90 分钟之间测量的定量K （放射性示踪剂在室之间的单向净流入率）和半定量肝脏 SUV（标准摄取值）之间的比较显示出使用后一个参数的潜力，从而避免了血液采样的需要作为K的替代物，用于监测 [ 18 F]阿托伐他汀的摄取。临床前试验显示，与雄性大鼠相比，雌性大鼠的摄取和清除速度更快，这似乎与动脉输入和肝组织之间的交换效率更高有关。由于[ 18 F]阿托伐他汀动力学缓慢，在研究的时间范围内肝脏和血浆浓度之间未达到平衡，因此难以获得足够且准确的动力学信息来定量表征放射性示踪剂随时间的药代动力学。尽管如此，报告的结果表明，只要所有扫描都在同一时间点进行，SUV 就有可能用作一种简化的措施。 [ 18 F]阿托伐他汀的临床前研究显示，与雄性大鼠相比，雌性大鼠的摄取和清除速度更快，这显然与动脉血和肝组织之间更高的交换效率有关。
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