Volume 2025, Issue 1 6685000

Research Article

Open Access

Design, Synthesis, Biological Evaluation, DFT Calculations, and Molecular Docking Investigations of ^99mTc-Rosuvastatin as a Promising Radiopharmaceutical for Liver Targeting

Corresponding Author

Moustapha Eid Moustapha

[email protected]

orcid.org/0000-0001-6668-0430

Department of Chemistry , College of Sciences and Humanities , Prince Sattam bin Abdulaziz University , Al-Kharj , 16273 , Saudi Arabia , psau.edu.sa

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El Hassane Anouar,

El Hassane Anouar

orcid.org/0000-0001-9240-7163

Department of Chemistry , College of Sciences and Humanities , Prince Sattam bin Abdulaziz University , Al-Kharj , 16273 , Saudi Arabia , psau.edu.sa

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Hend Fayez,

Hend Fayez

Labeled Compounds Department , Egyptian Atomic Energy Authority (EAEA) , P.O. Box 13759, Cairo , Egypt

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Moustapha Eid Moustapha,

Corresponding Author

Moustapha Eid Moustapha

[email protected]

orcid.org/0000-0001-6668-0430

Department of Chemistry , College of Sciences and Humanities , Prince Sattam bin Abdulaziz University , Al-Kharj , 16273 , Saudi Arabia , psau.edu.sa

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El Hassane Anouar,

El Hassane Anouar

orcid.org/0000-0001-9240-7163

Department of Chemistry , College of Sciences and Humanities , Prince Sattam bin Abdulaziz University , Al-Kharj , 16273 , Saudi Arabia , psau.edu.sa

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Hend Fayez,

Hend Fayez

Labeled Compounds Department , Egyptian Atomic Energy Authority (EAEA) , P.O. Box 13759, Cairo , Egypt

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First published: 19 May 2025

https://doi.org/10.1155/joch/6685000

Academic Editor: Mahmood Ahmed

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Abstract

Rosuvastatin is a lipid-lowering medication belonging to the statin group that acts as a selective inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting step of cholesterol biosynthesis in the liver. ^99mTc-rosuvastatin was synthesized aiming to develop a potential radiopharmaceutical for targeting liver. The in vitro stability and radiochemical yield were investigated, and the yield of the ^99mTc-rosuvastatin complex was 89.5 ± 1.85%. Biodistribution study revealed a good preferential localization of ^99mTc-rosuvastatin in liver tissues suggesting using the labeled compound as a promising liver imaging candidate. The favorable sites of Tc labeling were determined by the analysis of natural atomic charges using the DFT method at the B3LYP/LanL2DZ level of theory. Binding modes between the rosuvastatin (and its stable technetium complex) and the human HMG-CoA reductase were determined using molecular docking, and the obtained results revealed the effectiveness of technetium in increasing the binding affinity to the active residues of HMG-CoA reductase.

1. Introduction

Rosuvastatin belongs to a well-known group of drugs called “statins” and is chemically described as a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor [1–3]. It showed more effective affinity for HMG-CoA enzyme active site than other statins [4–6]. It works specifically in the liver to prevent the production of cholesterol and HMG-CoA reductase [7–9]. Rosuvastatin works in the liver as a selective HMG-CoA reductase inhibitor and cholesterol biosynthesis [10, 11]. Lipophilicity/hydrophilicity is possibly the most important physicochemical property of a potential drug [12–15]. Rosuvastatin is a relatively hydrophilic statin (logD = −033) at pH 7.4 [16–19] due to the presence of polar methyl sulfonamide moiety [20] and not significantly metabolized by cytochrome P450 (CYP) enzyme [21]. The greater hydrophilicity of rosuvastatin compared to other statins makes it more hepatoselective, and the high rate of uptake is observed only in the major parenchymal cells of the liver called hepatocytes either by passive diffusion and/or active transport at low concentrations compared with nonhepatic cells [22]. Selective hepatic uptake and distribution of rosuvastatin via organic anion transporters contributed to its high pharmacological activity [23, 24]. Radiolabeling of aromatic compounds is a common technique used to produce potential bioactive molecules and radiopharmaceuticals [25–29]. Technetium-99m radiopharmaceuticals are used in morphological and dynamic imaging of many body organs, for the diagnosis of various diseases. Many different technetium imaging agents have been developed and introduced into clinical practice for the diagnosis of human body organs related to the liver, kidney, heart, brain, thyroid, lung, and tumor diseases [30–33].

The pharmacokinetics of rosuvastatin, labeled with carbon-14 (¹⁴C), have been studied in both animal and human models. In mice, the hepatic uptake rate of ¹⁴C-rosuvastatin was determined to be 0.885 mL/min/g tissue, indicating a comparatively high selective uptake within the liver relative to other statin compounds. Furthermore, the drug exhibited a diffusion rate of 3.3 × 10⁵ particles/mm² into hepatic tissue, suggesting a pronounced propensity for hepatic distribution [34]. In human studies involving healthy adult male volunteers, approximately 50% of the administered ¹⁴C-rosuvastatin dose was absorbed. Analysis of radiolabeled material recovered within 72 h postadministration revealed that 70% of the dose was accounted for. The primary route of elimination was hepatobiliary excretion, with 90% of the recovered dose found in feces. Renal excretion accounted for the remaining 10%, as evidenced by urinary recovery. These findings suggest that metabolism plays a minor role in the clearance of rosuvastatin, with direct excretion via the hepatobiliary system being the dominant elimination pathway [35–37].

This research focused on the development and preclinical characterization of a technetium-99m (^99mTc)-labeled rosuvastatin as a potential hepatotropic radiopharmaceutical. The objectives included the synthesis of ^99mTc-rosuvastatin to establish and optimize a robust radiolabeling protocol with comprehensive characterization of the resulting radiocomplex. Characterization studies included radiochemical purity, in vitro stability, and pharmacokinetic and biodistribution to evaluate the in vivo biological behavior of ^99mTc-rosuvastatin. The comprehensive goal is to determine the suitability of ^99mTc-rosuvastatin as a diagnostic imaging agent for hepatic pathologies based on its selective accumulation within liver tissue.

2. Materials and Methods

2.1. Chemicals and Instruments

Rosuvastatin (C₂₂H₂₈FN₃O₆S) (M.wt. = 481.5 g/mol) was a generous contribution from EIPICO, Egypt. Chromatography papers (Whatman No. 1) were obtained from Whatman International Ltd, UK. Technetium-99m was supplied from a ⁹⁹Mo/^99mTc generator (Gentech, Turkey) and eluted as ^99mTcO₄⁻. We obtained Sodium borohydride (NaBH₄; 37.83 g/mol) from Sigma-Aldrich. In all experiments, deionized (DI) water was utilized to prepare solutions. All reagents and solvents were of high purity and consumed without further purification. The radioactivity was measured in a well-type NaI (Tl) scintillation detector coupled to a digital scaler ratemeter SR7 model, UK.

2.2. Synthesis of ^99mTc-Rosuvastatin

The effect of different reaction parameters on the radiolabeling efficiency of rosuvastatin, such as the amount of rosuvastatin (100–2000 μg), the amount of reducing agent (NaBH₄; 10–150 mg), the reaction pH (2–11), and reaction time (5–60 min), was examined to optimize the reaction conditions to increase the radiolabeling yield. An amount of 60 mg NaBH₄ (15.8 mM) and 500 μg rosuvastatin dissolved in deoxygenated water (10 mM) was carried to a reaction vial and mixed with 100 μL of a recently eluted ^99mTcO₄⁻ (400 MBq). The reaction was stirred regularly for 30 min at room temperature. The pH of the reaction medium was adjusted to 9 with phosphate buffer.

2.3. Radiochemical and Analytical Methods of Analysis

The labeling efficiency of ^99mTc-rosuvastatin compound was carried out by ascending paper chromatography to estimate the percentage of ^99mTc-rosuvastatin, free pertechnetate, and reduced hydrolyzed ^99mTc colloidal species. Samples are positioned 2 cm over the bottom margin of the chromatography strip (13 cm length, 1 cm width). The paper strip was developed with a mixture of ammonia:water:ethanol (1:5:2), while the other strip was developed with acetone. After complete development, the two strips were dried, cut into 1-cm pieces, and then individually counted using a NaI (Tl) scintillation detector coupled to gamma-ray counter to determine the ratio of free ^99mTcO₄, ^99mTc-rosuvastatin complex, and the hydrolyzed ^99mTc.

The radiochemical yield was illustrated as the ratio of ^99mTc-rosuvastatin radioactivity to the entire radioactivity multiplied by 100. The yield was the average of three experiments. The complex was analyzed chromatographically using a sodium iodide radiometric detector connected to an Agilent HPLC system. An aliquot of 10 μL ^99mTc-rosuvastatin was injected under optimal conditions into a reversed phase C18 Waters column (4.6 × 150 mm, 5 μm) kept at 25°C with a mobile phase containing 0.1% triethylamine in water modified to pH 4.5 using acetonitrile/methanol and glacial acetic acid (55:45; v/v). The mobile phase was filtered, degassed, and then pumped at a flow rate of 1 mL/min. Rosuvastatin was determined by UV absorbance at 242 nm.

2.4. In Vitro Stability of ^99mTc-Rosuvastatin

The complex’s in vitro stability was performed by incubating the reaction mixture with 1 mL of normal serum at 37°C for 24 h. Aliquots of exactly 2–3 μL were extracted and tested at different time periods using paper chromatography to find out the percentage of ^99mTc-rosuvastatin and ^99mTcO₄⁻. Therefore, the stability of the radiolabeled compound will define its convenience for in vivo application.

2.5. Lipophilicity/Hydrophilicity

The lipophilicity/hydrophilicity (partition coefficient logD) of ^99mTc-rosuvastatin was measured experimentally at pH 7.4. Simply add an aliquot of 1 mL of the complex along with 5 mL of octanol and water to a centrifuge tube. After shaking the mixture for 5 min, it was centrifuged at 4500 rpm for 10 min. After separating the two phases, 500 μL aliquots of each phase were withdrawn and counted in a gamma counter. Extraction was carried out in triplicate and the partition coefficient (logD) was estimated as the ratio of the radioactive complex in both octanol and water phase at equilibrium.

2.6. Animal Studies

Biodistribution studies were performed in accordance with the Egyptian Atomic Energy Authority guidelines and were licensed by the Animal Care Committee of the Labeled Compounds Department. Albino mice (26–35 g) were housed in groups of five (n = 5). Mice were administered with 10 μL of the pure labeled compound intravenously via the tail vein (0.3 MBq/g). Mice under anesthesia were sacrificed at 0.25, 0.5, 1, 2, and 4 h after administration of ^99mTc-rosuvastatin. After sacrifice, each mouse was weighed and dissected, and blood was extracted from the heart. Saline was used to wash organs and tissues, which were then collected and weighed in plastic containers. Each sample’s radioactivity and background were calculated using a NaI (Tl) detector-based well counter. In a group of five mice per time point, biodistribution data were reported as a percentage of the injected dose per organ (%ID/organ ± SD). Predosing the mice with nonradioactive rosuvastatin 0.5 h before the injection of ^99mTc-rosuvastatin was expressed as average percentage of hepatic uptake at 0.5 h postinjection (n = 5). The ANOVA test was applied to determine statistical significance in tissue uptake, and all data are presented as mean ± SD [38].

2.7. DFT Calculations

Calculations of technetium complexes with rosuvastatin have been performed using density functional calculation (DFT) method at the B3LYP/LANL2DZ level of theory for geometry prediction and frequency as implemented in the Gaussian 16 software [39]. Optimized geometries were sitting at true minima. Favorable coordinates sites of rosuvastatin with technetium were determined by the analysis of natural atomic charge (NPA) of the former obtained at the same level of theory.

2.8. Molecular Docking

To determine how the rosuvastatin and its technetium complexes bind to the human HMG-CoA reductase, AutoDock package was used to study the molecular docking [40]. The initial geometries of HMG-CoA reductase and the originally docked ligand, rosuvastatin (PDB code: 1HWL), were retrieved from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank website [41]. Favorable active sites were recognized based on co-crystallized HMG-CoA reductase-rosuvastatin complex structure of target protein. The re-docking of the original rosuvastatin ligands into the active sites was relatively reproduced with root mean square deviation (RMSD) values of 0.492, 1.252, 1.199, and 0.982 Å. The technetium rosuvastatin complexes were docked into the active site of the lowest RMSD value. The molecular docking step was described in preceding work [42]. Docking calculations were performed using a workstation computer equipped with an Intel Xeon Gold 6130 CPU Processor 16 Core 2.10 GHz.

3. Results and Discussion

3.1. Coupling of Rosuvastatin and Technetium-99m

Coupling of rosuvastatin and technetium-99m (t_1/2 = 6 h) was performed via direct radiolabeling process. The radiochemical synthesis of ^99mTc-rosuvastatin was optimized by studying different reaction parameters (Figure 1) such as the effect of amount, reducing agent, pH, and time. The optimum amount (Figure 1(a)) of ligand required to obtain maximum radiochemical yield (89.5%) was exactly 500 μg. Below this value, the rosuvastatin amount was insufficient to react with all the reduced ^99mTc. At higher amount, the labeling yield was stable up to 1000 μg. The radiochemical yield was dependent on the amount of reducing agent (NaBH₄) present in the reaction mixture. Sodium borohydride (NaBH₄) was selected as a good reducing agent to prevent the interference of colloidal tin (IV) oxide (SnO₂) in the tin (II) chloride (SnCl₂) procedure. According to Figure 1(b), an amount of 100 μg was sufficient to reduce the present technetium-99m to the desirable pertechnetate (^99mTcO₄⁻). At lower amounts (10–25 μg), the yield decreased due to the large percentage of free ^99mTcO₄⁻ while at higher amounts (110–150 μg) of reducing agent, the yield decreased dramatically to 73%. This decline may be due to the formation of undesirable colloids, which can compete with rosuvastatin for reduced technetium-99m. The effect of pH (Figure (1c)) on the radiochemical yield was studied to determine the optimum pH for maximum radiolabeling yield. At pH 9, the highest radiochemical yield was attained due to the strong reducing power of NaBH₄ in alkaline medium [43, 44] reducing all pertechnetates to lower oxidation state technetium favoring the formation of ^99mTc-rosuvastatin. The labeling percentage decreased to 78% at low pH (2–4) due to the destructive ability of the reducing agent. At pH above 9, the yield decreased to 78.2% due to the formation of the reduced hydrolyzed technetium-99m as the main impurity in the process, which did not bind to the rosuvastatin molecule. The labeling yield increased when increasing the reaction time from 5 to 30 min (Figure 1(d)), which was enough to complete the reaction.

Details are in the caption following the image — **Figure 1 (a)**
Open in figure viewer PowerPoint

^99mTc-rosuvastatin yields vs. (a) rosuvastatin amount; (b) reducing agent amount; (c) reaction pH; (d) reaction time.

In paper chromatography developed with acetone as the solvent, free ^99mTcO₄⁻ (R_f = 1) migrated with the solvent front, whereas the radiolabeled rosuvastatin and reduced hydrolyzed technetium stayed at the base. The second paper strip was developed using a combination of ammonia:water:ethanol (1:5:2), where ^99mTc-rosuvastatin and free ^99mTcO₄⁻ species moved with different solvent fronts while hydrolyzed reduced technetium-99m colloid (TcO₂) remained at the origin (R_f = 0). Radiochemical purity was estimated by subtracting the total of free pertechnetate and colloid percentages from 100%. Furthermore, it was confirmed through chromatographic analysis using HPLC, where the retention times of free technetium and ^99mTc-rosuvastatin were 1.25 and 4.5 min, respectively, as indicated in the chromatogram (Figure 2).

The appropriate injection time was determined based on the in vitro stability of ^99mTc-rosuvastatin to prevent the formation of unwanted products due to radiolysis of the radiolabeled compound. In vitro stability results revealed that ^99mTc-rosuvastatin remained stable in serum for up to 24 h.

The hydrophilicity/lipophilicity determines the binding affinity of the labeled compound and affects its hepatocyte uptake and excretion rate. The lipophilicity was measured by determining the separation of ^99mTc-rosuvastatin between n-octanol and water solution in the physiologically relevant pH range (7.4). The experimental logD of the labeled compound (−0.34 ± 0.02) was found to be greater than the logD value of rosuvastatin (−0.33), which may be owing to the coupling of technetium to the structure. The negative value of logD of the labeled complex would lead to determine that ^99mTc-rosuvastatin would be of lower lipophilicity and more likely to be water soluble in the body. The characteristic methane sulfonamide group in the complex enhanced hydrophilicity and led to an improved ionic binding interaction with the HMG-CoA enzyme. Therefore, the retention time of rosuvastatin was observed before ^99mTc-rosuvastatin on a reversed-phase high-performance liquid chromatogram (RP-HPLC), as shown in Figure 2. The relative hydrophilic character of ^99mTc-rosuvastatin is vital in predicting the uptake and excretion pathway implying attenuated access to nonhepatic cells because of low passive diffusion and considerable hepatic cell uptake via selective organic anion transport.

3.2. Biodistribution Studies

The biodistribution and retention of ^99mTc-rosuvastatin were studied by tracking the compound in various organs of mice following intravenous injection. No adverse effects such as pain, redness, edema, or death were observed in the injected mice. Figure 3 shows a high and steady activity in blood after IV injection throughout the study period, with slow clearance due to the ninety percent binding of rosuvastatin to blood proteins [17, 20]. ^99mTc-rosuvastatin was efficiently eliminated from the bloodstream, leaving only 1.53% ± 0.15% in the blood after 4 h postinjection compared to 15.42% ± 0.05% at 0.25 h postinjection. The liver-targeting ability of ^99mTc-rosuvastatin revealed a high uptake in the liver of 50.0 ± 0.45% at 0.25 h postinjection, then increased to reach 53.15% ± 0.56% after 0.5 h, and then decreased to 45.34% ± 1.12% after 2 h. These results revealed the stability of ^99mTc-rosuvastatin for several hours and demonstrated the ability to bind to the active site of HMG-CoA in vivo with high affinity and specificity as a liver imaging agent, suggesting the use of the labeled compound as a promising candidate for liver imaging. The relatively high hydrophilicity of rosuvastatin compared to other statins may explain the minor nonspecific distribution to extrahepatic tissues and may be consistent with low uptake in other organs. The effectiveness of hepatocyte uptake and the clearance rate may be dependent on the physiochemical and structural relationship between the lipophilic and hydrophilic functional groups on ^99mTc-rosuvastatin. The absorption in the intestine was 11.42 ± 0.32% at 0.25 h and increased to 12.61 ± 0.49% at 0.5 h, which assumed that the clearance pathway proceeded through the hepatobiliary excretory route via the intestine. The labeled compound displayed accumulation in the kidneys (3.46% ± 0.34% at 0.5 h and 7.56% ± 0.01% at 1 h) supporting a second elimination route through the urinary renal excretory system. It is clear from the clearance model in mice that ^99mTc-rosuvastatin was effectively cleared via the hepatobiliary excretory pathway (liver and intestine) and through the renal urinary system to a lesser extent. The radioactivity retained in the stomach was 0.45% ± 0.25% at 0.5 h as compared to 0.12% ± 0.02% at 4 h confirming suitable in vivo stability and negligible dissociation due to metabolism. Predosing mice with nonradioactive rosuvastatin 0.5 h before administration of ^99mTc-rosuvastatin inhibited the liver uptake to 15.43 ± 0.34% ID/organ. A similar hepatocellular-targeted radiolabeled ^99mTc-atorvastatin has been prepared with radiolabeling efficiency of 90.3% to target and selectively image the liver or hepatocellular carcinoma. The maximum liver uptake was 37.6% ID/g within 15 min [45], indicating a higher hepatic uptake efficiency of ^99mTc-rosuvastatin compared to a compound from the same class of statins. This suggests the use of ^99mTc-rosuvastatin compound as a promising selective candidate for liver imaging.

3.3. DFT Results

Fukui indices were calculated to elucidate the structure, which was confirmed by DFT calculation applying the hybrid functional B3LYP together with LanL2DZ basis set in gas and in a polarizable continuum model (PCM), in which IEF-PCM formalisms were evaluated. Figure 4 represents the optimized geometries of TcR1 and TcR2 complexes. NPA analysis revealed that technetium may coordinate to two main sets of rosuvastatin atomic sites. In the TcR1 complex, Tc is coordinated to O57 and O31 atomic sites (NPAs of −0.838 and −0.783) of rosuvastatin, while in the TcR2 complex, it is coordinated to O56 and O57 atomic sites (NPAs of −0.826 and −0.838). The calculated free Gibbs energy change of the two complexes revealed that TcR2 is thermodynamically more stable than TcR1 with a relative Gibbs energy of 8 kcalmol⁻¹.

3.4. Molecular Docking

The intermolecular interactions between rosuvastatin and its technetium complexes were determined by analyzing the docking outputs into HMG-CoA reductase active site. Table 1 outlines the predicted binding free energies (kcal/mol) of the stable ligand-receptor (LR) complexes and number of conventional intermolecular hydrogen bonds (HBs) formed between rosuvastatin and its technetium complexes on one side and HMG-CoA reductase active site residues on the other side. The docking results showed that the complexes formed between rosuvastatin and its technetium complexes and the active residues exhibited negative binding energies, revealing that the inhibition of the target receptor was both thermodynamically and spontaneously favorable (Table 1). Docking analysis revealed that the coordination position of technetium with rosuvastatin may have a strong effect on its binding to the active residues of HMG-CoA reductase (Figure 5). It stabilized the TcR2-HMG-CoA reductase complex by 0.41, while destabilizing TcR1-HMG-CoA reductase by 0.81 kcalmol⁻¹.

Table 1. Docking binding energies (kcal/mol), conventional hydrogen bonding (HBs), and number of closest residues to the docked rosuvastatin and its technetium complex into HMG-CoA reductase active site.

	Free binding energy (kcal/mol)	Conventional H-bonds (HBs)	Number of closest residues to the docked compounds
Rosuvastatin	−9.42	7	13
TcR1	−8.61	10	13
TcR2	−9.83	6	11

4. Conclusions

^99mTc-rosuvastatin was successfully prepared using direct labeling technique with a radiochemical yield of 89.5 ± 1.8%. Molecular docking predicted the binding affinity of ^99mTc-rosuvastatin to the human HMG-CoA enzyme binding sites in the liver. Biodistribution results showed that ^99mTc-rosuvastatin has a high targeting ability toward hepatocytes compared to nonhepatic tissues indicating that the new couple is a promising radiopharmaceutical for liver imaging.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding

This study was supported by the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia, project number 2022/01/20095.

Acknowledgments

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia, for funding this research work through the project number 2022/01/20095.

Open Research

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

1 Mostaza J. and Escobar C., Rosuvastatin-Based Lipid-Lowering Therapy for the Control of LDL Cholesterol in Patients at High Vascular Risk, Journal of Clinical Medicine. (2024) 13, no. 7, 1894–1906, https://doi.org/10.3390/jcm13071894.
10.3390/jcm13071894
CAS PubMed Google Scholar
2 Yokohama K., Fukunishi S., Ii M. et al., Rosuvastatin as a Potential Preventive Drug for the Development of Hepatocellular Carcinoma Associated With Non-Alcoholic Fatty Liver Disease in Mice, International Journal of Molecular Medicine. (2016) 38, no. 5, 1499–1506, https://doi.org/10.3892/ijmm.2016.2766, 2-s2.0-84992702688.
10.3892/ijmm.2016.2766
CAS PubMed Google Scholar
3 Kitamura S., Maeda K., Wang Y., and Sugiyama Y., Involvement of Multiple Transporters in the Hepatobiliary Transport of Rosuvastatin, Drug Metabolism and Disposition: The Biological Fate of Chemicals. (2008) 36, no. 10, 2014–2023, https://doi.org/10.1124/dmd.108.021410, 2-s2.0-52949104006.
10.1124/dmd.108.021410
CAS PubMed Google Scholar
4 White C. M., A Review of the Pharmacologic and Pharmacokinetic Aspects of Rosuvastatin, The Journal of Clinical Pharmacology. (2002) 42, no. 9, 963–970.
10.1177/009127000204200902
CAS PubMed Web of Science® Google Scholar
5 Bousquet P. and Gayet J. L., Pharmacologic Characteristics of Rosuvastatin, a New HMG-CoA Reductase Inhibitor, Therapie. (2003) 58, no. 2, 113–121, https://doi.org/10.2515/therapie:2003016, 2-s2.0-0041654460.
10.2515/therapie:2003016
PubMed Google Scholar
6 Olsson A. G., McTaggart F., and Raza A., Rosuvastatin: A Highly Effective New HMG-CoA Reductase Inhibitor, Cardiovascular Drug Reviews. (2002) 20, no. 4, 303–328, https://doi.org/10.1111/j.1527-3466.2002.tb00099.x.
10.1111/j.1527-3466.2002.tb00099.x
CAS PubMed Web of Science® Google Scholar
7 Bowman C. M., Ma F., Mao J., and Chen Y., Examination of Physiologically-Based Pharmacokinetic Models of Rosuvastatin, CPT: Pharmacometrics & Systems Pharmacology. (2021) 10, no. 1, 5–17, https://doi.org/10.1002/psp4.12571.
10.1002/psp4.12571
CAS PubMed Web of Science® Google Scholar
8 Kanukula R., Salam A., Rodgers A., and Kamel B., Pharmacokinetics of Rosuvastatin: A Systematic Review of Randomised Controlled Trials in Healthy Adults, Clinical Pharmacokinetics. (2021) 60, no. 2, 165–175, https://doi.org/10.1007/s40262-020-00978-9.
10.1007/s40262-020-00978-9
CAS PubMed Google Scholar
9 González R., Peña M. Á., Torres N. S., and Torrado G., Design, Development, and Characterization of Amorphous Rosuvastatin Calcium Tablets, PLoS One. (2022) 17, no. 3, https://doi.org/10.1371/journal.pone.0265263.
10.1371/journal.pone.0265263
Google Scholar
10 Cheng J. W., Rosuvastatin in the Management of Hyperlipidemia, Clinical Therapeutics. (2004) 26, no. 9, 1368–1387, https://doi.org/10.1016/J.Clinthera.2004.09.005, 2-s2.0-9644288286.
10.1016/J.Clinthera.2004.09.005
CAS PubMed Google Scholar
11 McTaggart F., Buckett L., Davidson R. et al., Preclinical and Clinical Pharmacology of Rosuvastatin, a New 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, The American Journal of Cardiology. (2001) 87, no. 5A, 28B–32B, https://doi.org/10.1016/s0002-9149(01)01454-0.
10.1016/s0002-9149(01)01454-0
CAS PubMed Google Scholar
12 Herbig M. E. and Evers D. H., Correlation of Hydrotropic Solubilization by Urea With logD of Drug Molecules and Utilization of This Effect for Topical Formulations, European Journal of Pharmaceutics and Biopharmaceutics. (2013) 85, no. 1, 158–160, https://doi.org/10.1016/j.ejpb.2013.06.022, 2-s2.0-84882992312.
10.1016/j.ejpb.2013.06.022
CAS PubMed Google Scholar
13 McTavish D. and Sorkin E. M., Pravastatin: A Review of its Pharmacologic Properties and Therapeutic Potential in Hypercholesterolemia, Drugs. (1991) 42, no. 1, 65–89, https://doi.org/10.2165/00003495-199142010-00005, 2-s2.0-0025830289.
10.2165/00003495-199142010-00005
CAS PubMed Google Scholar
14 Rees S., Statins: All You Need to Know, Nurse Prescribing. (2017) 15, no. 5, https://doi.org/10.12968/npre.2017.15.5.230.
10.12968/npre.2017.15.5.230
Google Scholar
15 Schachter M., Chemical, Pharmacokinetic and Pharmacodynamic Properties of Statins: An Update, Fundamental & clinical Pharmacology. (2005) 19, no. 1, 117–125, https://doi.org/10.1111/j.1472-8206.2004.00299.x, 2-s2.0-13444251203.
10.1111/j.1472-8206.2004.00299.x
CAS PubMed Web of Science® Google Scholar
16 J Warwick M., Dane A. L., Ali R., and Schneck D. W., Single and Multiple Dose Pharmacokinetics and Safety of the New HMG CoA Reductase Inhibitor ZD4522, Atherosclerosis. (2000) 151, https://doi.org/10.1016/S0021-9150(00)80175-6.
10.1016/S0021-9150(00)80175-6
Google Scholar
17 Martin P. D., Mitchell P. D., and Schneck D. W., Pharmacodynamic Effects and Pharmacokinetics of a New HMG-CoA Reductase Inhibitor, Rosuvastatin, After Morning or Evening Administration in Healthy Volunteers, British Journal of Clinical Pharmacology. (2002) 54, no. 5, 472–477, https://doi.org/10.1046/j.1365-2125.2002.01688.x, 2-s2.0-0036432991.
10.1046/j.1365-2125.2002.01688.x
CAS PubMed Web of Science® Google Scholar
18 Zhu K. W., Wang G. M., Li C. Y. et al., Pharmacokinetics and Bioequivalence of Two Formulations of Rosuvastatin Following Single-Dose Administration in Healthy Chinese Subjects Under Fasted and Fed Conditions, Clinical Pharmacology in Drug Development. (2022) 11, no. 8, 987–996, https://doi.org/10.1002/cpdd.1112.
10.1002/cpdd.1112
CAS PubMed Web of Science® Google Scholar
19 Lehtisalo M., Taskinen S., Tarkiainen E. K. et al., A Comprehensive Pharmacogenomic Study Indicates Roles for SLCO1B1, ABCG2 and SLCO2B1 in Rosuvastatin Pharmacokinetics, British Journal of Clinical Pharmacology. (2023) 89, no. 1, 242–252, https://doi.org/10.1111/bcp.15485.
10.1111/bcp.15485
CAS PubMed Web of Science® Google Scholar
20 McTaggart F., Comparative Pharmacology of Rosuvastatin, Atherosclerosis Supplements. (2003) 4, no. 1, 9–14, https://doi.org/10.1016/s1567-5688(03)00004-7, 2-s2.0-0141560665.
10.1016/s1567-5688(03)00004-7
CAS PubMed Google Scholar
21 Martin P. D., Warwick M. J., Dane A. L. et al., Metabolism, Excretion, and Pharmacokinetics of Rosuvastatin in Healthy Adult Male Volunteers, Clinical Therapeutics. (2003) 25, no. 11, 2822–2835, https://doi.org/10.1016/s0149-2918(03)80336-3, 2-s2.0-0344664550.
10.1016/s0149-2918(03)80336-3
CAS PubMed Google Scholar
22 Kimoto E., Vourvahis M., Scialis R. J., Eng H., Rodrigues A. D., and Varma M. V. S., Mechanistic Evaluation of the Complex Drug-Drug Interactions of Maraviroc: Contribution of Cytochrome P450 3A, P-Glycoprotein and Organic Anion Transporting Polypeptide 1B1, Drug Metabolism & Disposition. (2019) 47, no. 5, 493–503, https://doi.org/10.1124/dmd.118.085241, 2-s2.0-85064110457.
10.1124/dmd.118.085241
CAS PubMed Google Scholar
23 Wang Q., Zheng M., and Leil T., Investigating Transporter-Mediated Drug-Drug Interactions Using a Physiologically Based Pharmacokinetic Model of Rosuvastatin, CPT: Pharmacometrics & Systems Pharmacology. (2017) 6, no. 4, 228–238, https://doi.org/10.1002/psp4.12168, 2-s2.0-85015235802.
10.1002/psp4.12168
CAS PubMed Google Scholar
24 Sanoh S., Naritomi Y., Kitamura S. et al., Predictability of Human Pharmacokinetics of Drugs that Undergo Hepatic Organic Anion Transporting Polypeptide (OATP)-Mediated Transport Using Single-Species Allometric Scaling in Chimeric Mice With Humanized Liver: Integration With Hepatic Drug Metabolism, Xenobiotica. (2020) 50, no. 11, 1370–1379, https://doi.org/10.1080/00498254.2020.1769229.
10.1080/00498254.2020.1769229
CAS PubMed Google Scholar
25 Moustapha M. E., Radioiodination of Atorvastatin as a Model Radiopharmaceutical for Targeting Liver, Radiochemistry. (2020) 62, no. 4, 532–538, https://doi.org/10.1134/S1066362220040104.
10.1134/S1066362220040104
Google Scholar
26 Moustapha M. E., Geesi M. H., Farag Z. R., and Anouar E. H., Electrophilic Aromatic Synthesis of Radioiodinated Aripiprazole: Experimental and DFT Investigations, Current Organic Synthesis. (2020) 17, no. 4, 295–303, https://doi.org/10.2174/1570179417666200409145824.
10.2174/1570179417666200409145824
CAS PubMed Google Scholar
27 Moustapha E. M., Geesi M., Zeinab R., and Hassane E., Anouar Organic Synthesis of Iodinated Atorvastatin via Nucleophilic Substitution Reaction: Experimental and DFT Studies, Current Organic Chemistry. (2018) 22, no. 20, 2017–2022, https://doi.org/10.2174/1385272822666180913111819, 2-s2.0-85062003269.
10.2174/1385272822666180913111819
CAS Google Scholar
28 Papagiannopoulou D., Technetium-99m Radiochemistry for Pharmaceutical Applications, Journal of Labelled Compounds and Radiopharmaceuticals. (2017) 60, no. 11, 502–520, https://doi.org/10.1002/jlcr.3531, 2-s2.0-85028475286.
10.1002/jlcr.3531
CAS PubMed Web of Science® Google Scholar
29 Mushtaq S., Bibi A., Park J. E., and Jeon J., Recent Progress in Technetium-99m-Labeled Nanoparticles for Molecular Imaging and Cancer Therapy, Nanomaterials. (2021) 11, https://doi.org/10.3390/nano11113022.
10.3390/nano11113022
Google Scholar
30 Trusova V., Karnaukhov I., Zelinsky A. et al., Radiolabeling of Bionanomaterials With Technetium 99m: Current State and Future Prospects, Nanomedicine. (2024) 19, no. 17, 1569–1580, https://doi.org/10.1080/17435889.2024.2368454.
10.1080/17435889.2024.2368454
PubMed Google Scholar
31 Crişan G., Moldovean-Cioroianu N. S., Timaru D. G., Andrieş G., Căinap C., and Chiş V., Radiopharmaceuticals for PET and SPECT Imaging: A Literature Review Over the Last Decade, International Journal of Molecular Sciences. (2022) 23, no. 9, https://doi.org/10.3390/ijms23095023.
10.3390/ijms23095023
Google Scholar
32 Bai J. W., Qiu S. Q., and Zhang G. J., Molecular and Functional Imaging in Cancer-Targeted Therapy: Current Applications and Future Directions, Signal Transduction and Targeted Therapy. (2023) 8, no. 1, https://doi.org/10.1038/s41392-023-01366-y.
10.1038/s41392-023-01366-y
Google Scholar
33 Dhoundiyal S., Srivastava S., Kumar S. et al., Radiopharmaceuticals: Navigating the Frontier of Precision Medicine and Therapeutic Innovation, European Journal of Medical Research. (2024) 29, no. 1, https://doi.org/10.1186/s40001-023-01627-0.
10.1186/s40001-023-01627-0
PubMed Google Scholar
34 Nezasa K., Higaki K., Matsumura T. et al., Liver-Specific Distribution of Rosuvastatin in Rats: Comparison With Pravastatin and Simvastatin, Drug Metabolism & Disposition. (2002) 30, no. 11, 1158–1163, https://doi.org/10.1124/dmd.30.11.1158, 2-s2.0-0036840329.
10.1124/dmd.30.11.1158
CAS PubMed Google Scholar
35 Nezasa K., Takao A., Kimura K., Takaichi M., Inazawa K., and Koike M., Pharmacokinetics and Disposition of Rosuvastatin, a New 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, in Rat, Xenobiotica. (2002) 32, no. 8, 715–727, https://doi.org/10.1080/00498250210144820, 2-s2.0-0036690999.
10.1080/00498250210144820
CAS PubMed Google Scholar
36 Song Y., Lim H.-H., Yee J., Yoon H.-Y., and Gwak H.-S., The Association Between ABCG2 421C>A (Rs2231142) Polymorphism and Rosuvastatin Pharmacokinetics: A Systematic Review and Meta-Analysis, Pharmaceutics. (2022) 14, no. 3, https://doi.org/10.3390/pharmaceutics14030501.
10.3390/pharmaceutics14030501
Google Scholar
37 Hirota T., Fujita Y., and Ieiri I., An Updated Review of Pharmacokinetic Drug Interactions and Pharmacogenetics of Statins, Expert Opinion on Drug Metabolism & Toxicology. (2020) 16, no. 9, 809–822, https://doi.org/10.1080/17425255.2020.1801634.
10.1080/17425255.2020.1801634
CAS PubMed Web of Science® Google Scholar
38 El-Marakby E. M., Fayez H., Motaleb M. A., and Mansour M., Atorvastatin-Loaded Cubosome: A Repurposed Targeted Delivery Systems for Enhanced Targeting against Breast Cancer, Pharmaceutical Development and Technology. (2024) 29, no. 3, 236–247, https://doi.org/10.1080/10837450.2024.2323620.
10.1080/10837450.2024.2323620
CAS PubMed Google Scholar
39 Frisch M., Trucks G., Schlegel H. et al., Gaussian 09, Revision D. 01, 2009, Gaussian, Inc.
Google Scholar
40 Morris G. M., Huey R., Lindstrom W. et al., AutoDock4 and AutoDockTools4: Automated Docking With Selective Receptor Flexibility, Journal of Computational Chemistry. (2009) 30, no. 16, 2785–2791, https://doi.org/10.1002/jcc.21256, 2-s2.0-70349932423.
10.1002/jcc.21256
CAS PubMed Web of Science® Google Scholar
41 Istvan E. S. and Deisenhofer J., Structural Mechanism for Statin Inhibition of HMG-CoA Reductase, Science. (2001) 292, no. 5519, 1160–1164, https://doi.org/10.1126/science.1059344, 2-s2.0-0035843962.
10.1126/science.1059344
CAS PubMed Web of Science® Google Scholar
42 Othman I. M., Gad-Elkareem M. A., Snoussi M., Aouadi K., and Kadri A., Novel Fused Pyridine Derivatives Containing Pyrimidine Moiety as Prospective Tyrosyl-tRNA Synthetase Inhibitors: Design, Synthesis, Pharmacokinetics and Molecular Docking Studies, Journal of Molecular Structure. (2020) 1219, https://doi.org/10.1016/j.molstruc.2020.128651.
10.1016/j.molstruc.2020.128651
Google Scholar
43 Minkina V. G., Shabunya S. I., Kalinin V. I., Martynenko V. V., and Smirnova A. L., Stability of Alkaline Aqueous Solutions of Sodium Borohydride, International Journal of Hydrogen Energy. (2012) 37, no. 4, 3313–3318.
10.1016/j.ijhydene.2011.10.068
CAS Google Scholar
44 Simagina V. I., Ozerova A. M., Komova O. V., and Netskina O. V., Recent Advances in Applications of Co-B Catalysts in NaBH₄-Based Portable Hydrogen Generators, Catalysts. (2021) 11, no. 2, https://doi.org/10.3390/catal11020268.
10.3390/catal11020268
Google Scholar
45 Yousry C., Farrag N. S., and Amin A. M., Radiolabeling of Statistically Optimized Nanosized Atorvastatin Suspension for Liver Targeting and Extensive Imaging of Hepatocellular Carcinoma, Journal of Drug Delivery Science and Technology. (2023) 80, https://doi.org/10.1016/j.jddst.2023.104171.
10.1016/j.jddst.2023.104171
Google Scholar

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Design, Synthesis, Biological Evaluation, DFT Calculations, and Molecular Docking Investigations of ^99mTc-Rosuvastatin as a Promising Radiopharmaceutical for Liver Targeting

Abstract

1. Introduction