Evaluation of Pharmacokinetics of Simvastatin and Its Pharmacologically Active Metabolite from Controlled-Release Tablets of Simvastatin in Rodent and Canine Animal Models

Shanmugam, Sumathi; Ryu, Jae-Kuk; Yoo, Sun-Dong; Choi, Han‐Gon; Woo, Jong-Soo

doi:10.4062/biomolther.2011.19.2.248

Cited by 4 publications

(3 citation statements)

References 27 publications

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“…For instance, in humans, pitavastatin has high bioavailability and a long half-life, while in dogs, pitavastatin has relatively high bioavailability, but its half-life is similar to that of other statins. 21,[29][30][31] Therefore, it remains unclear whether the present results reflect the efficacy of statins against tumours in vivo, hence further in vivo investigations remain warranted to elucidate the most effective statin in dogs.…”

Section: Discussionmentioning

confidence: 91%

Comparison of the anticancer effects of various statins on canine oral melanoma cells

Ishikawa,

Irie,

Tashiro

et al. 2023

Vet Comparative Oncology

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Canine oral melanoma is a highly malignant cancer with a poor prognosis. Statins, commonly used drugs for treating dyslipidemia, exhibit pleiotropic anticancer effects and marked anti‐proliferative effects against melanoma cells. The anticancer effects among statins vary; in human cancers, lipophilic statins have shown stronger anticancer effects compared with hydrophilic statins. However, data on the differences in the effects of various statins on canine cancer cells are lacking, hence the optimal statins for treating canine melanoma remain unknown. Therefore, this study aimed to clarify the most effective statin by comparing the anticancer effects of hydrophilic rosuvastatin and lipophilic atorvastatin, simvastatin, fluvastatin and pitavastatin on three canine oral melanoma cell lines. Time‐dependent measurement of cell confluence showed that lipophilic statins had a stronger anti‐proliferative effect on all cell lines than hydrophilic rosuvastatin. Quantification of lactate dehydrogenase release, an indicator of cytotoxicity, showed that lipophilic statins more effectively induced cell death than hydrophilic rosuvastatin. Lipophilic statins affected both inhibition of cell proliferation and induction of cell death. The anticancer effects of statins on canine oral melanoma cells differed in the following ascending order of IC50 values: pitavastatin < fluvastatin = simvastatin < atorvastatin < rosuvastatin. The required concentration of pitavastatin was approximately 1/20th that of rosuvastatin. Among the statins used in this study, pitavastatin had the highest anticancer effect. Our results suggest lipophilic pitavastatin as the optimal statin for treating canine oral melanoma.

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Section: Discussionmentioning

confidence: 91%

Comparison of the anticancer effects of various statins on canine oral melanoma cells

Ishikawa,

Irie,

Tashiro

et al. 2023

Vet Comparative Oncology

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“… 5 However, in this study, the C max of SIM was reduced 5-fold compared to the reported C max value. 34 The current formulation was designed so that it could release AML-B but withhold release of SIM after about 8 h. Thus, reduction in C max was likely due to its delayed release till 8 h, though further proof is required to substantiate the hypothesis. The in-vitro release data revealed successful achievement of this aim of dosage form development which was supported by the pharmacokinetic study as well.…”

Section: Resultsmentioning

confidence: 99%

“…AUC 0-∞ of SIM in the current study was reduced 2-fold compared to reported values. 34 Immediate release formulations can potentially lead to the saturation of intestinal metabolic enzymes, subsequently leading to an enhanced bioavailability. 35 , 36 SIM is subjected to pre-systemic metabolism mainly by CYP 3A4 located in the enterocytes.…”

Section: Resultsmentioning

confidence: 99%

Fixed Dose Single Tablet Formulation with Differential Release of Amlodipine Besylate and Simvastatin and Its Pharmacokinetic Profile: QbD and Risk Assessment Approach

Kanwal

Mukhtar

Waheed

et al. 2021

DDDT

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Purpose A differential release fixed dose matrix tablet of amlodipine besylate (AML-B) and simvastatin (SIM) was formulated to enhance patient compliance. Material and Method In the first phase, release controlling parameters of AML-B and SIM granules were identified and in the second phase a fixed dose AML-B and SIM tablet formulation was prepared and optimized for a differential release of the drugs using a quality by design (QbD) and risk assessment approach. A validated HPLC method was employed for simultaneous determination of AML-B and SIM for FDC formulation. A pharmacokinetics of the above drugs was studied in healthy dogs in the third phase. Results In QbD-based optimized formulation, Eudragit ® RSPO-dicalcium phosphate (DCP) blend controlled the release of AML-B over 8 h, though this diffusion-controlled release assumed first order kinetics. DCP and Eudragit ® RS 100 also retarded release of SIM causing SIM release over 8 h after AML-B release from the optimized FDC tablet formulation. The HPLC retention times of AML-B and SIM were 2.10 and 15.52 min, respectively. Linearity for AML-B was 5.0–50 ng/mL and 0.01–2.0 µg/mL for SIM with percent recoveries of 92.85–101.53% and 94.51–117.75% for AML-B and SIM. AUC 0-∞ of AML-B was increased 3 fold, while AUC 0-∞ of SIM was decreased 2 fold. The t max values for AML-B and SIM were 12 and 6 h, respectively. AML-B was absorbed without any lag time (t lag ) while t lag was 6.33 ± 0.81 h for SIM, thus met the study objective. Conclusion The pharmacokinetic study showed an immediate absorption of AML-B while that of SIM was withheld for 6 h, close to the desired delay time of 8 h.

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Prodrugs: Harnessing chemical modifications for improved therapeutics

Kumar,

Kaur,

Kaur

et al. 2023

Journal of Drug Delivery Science and Technology

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Evaluation of Pharmacokinetics of Simvastatin and Its Pharmacologically Active Metabolite from Controlled-Release Tablets of Simvastatin in Rodent and Canine Animal Models

Cited by 4 publications

References 27 publications

Comparison of the anticancer effects of various statins on canine oral melanoma cells

Comparison of the anticancer effects of various statins on canine oral melanoma cells

Fixed Dose Single Tablet Formulation with Differential Release of Amlodipine Besylate and Simvastatin and Its Pharmacokinetic Profile: QbD and Risk Assessment Approach

Prodrugs: Harnessing chemical modifications for improved therapeutics

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