Simultaneous analysis of the total plasma concentration of atorvastatin and its five metabolites and the unbound plasma concentration of atorvastatin: Application in a clinical pharmacokinetic study of single oral dose

Cestari, Roberta Natália; Rocha, Adriana; Marques, Maria Paula; Oliveira, Renê Donizeti Ribeiro de; Lanchote, Vera Lúcia

doi:10.1016/j.jchromb.2019.121766

Cited by 5 publications

(3 citation statements)

References 15 publications

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“…ATV and its two active metabolites o-hydroxyatorvastatin (o-OH-ATV) and p-hydroxyatorvastatin (p-OH-ATV) are responsible for its HMG-CoA (3-hydroxy-3-methylglutaryl CoA) reductase inhibitory activity, while the corresponding inactive lactone form (LAC) was associated with myopathy [ 39 ].Our in vivo study firstly proved that ATV inhibited ferroptosis in I/R rat myocardium. However, its drug metabolism and stability in rats still need to be further evaluated.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin Inhibits Ferroptosis of H9C2 Cells by regulatingSMAD7/Hepcidin Expression to Improve Ischemia-Reperfusion Injury

Peng

Liao

Zhou

et al. 2022

Cardiology Research and Practice

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Background. Ferroptosis plays a key role in cardiomyopathy. Atorvastatin (ATV) has a protective effect on ischemia-reperfusion (I/R) cardiomyopathy. The purpose of this study is to elucidate the mechanism of ATV in I/R injury. Methods. H9C2 cells and cardiomyopathy rats were induced by hypoxia/reoxygenation (H/R) and I/R to construct in vitro and in vivo models. Cell viability was determined by CCK8. Cardiac histopathology was observed by HE staining. Transmission electron microscope (TEM) was used to observe the mitochondrial morphology. The reactive oxygen species (ROS) content in cells was analyzed by the biochemical method. ELISA was conducted to calculate the concentrations of total iron/Fe2+ and hepcidin. The expression of ferroptosis and SMAD pathway-related genes were detected by qPCR. Western blot was performed to detect the expression levels of ferroptosis and SMAD pathway-related proteins. Results. In H9C2 cells, ATV reversed the decline in cell viability, mitochondrial shrinkage, and ROS elevation induced by erastin or H/R. The concentration of total iron and Fe2+ in H/R-induced H9C2 cells increased, and the protein expression of FPN1 decreased. After ATV treatment, the concentration of total iron and Fe2+ decreased, and the protein expression of FPN1 increased. The expression of the SMAD7 gene in H/R-induced H9C2 cells decreased, and the expression of the hepcidin gene increased, which were reversed by ATV. When SMAD7 was knocked down, ATV treatment failed to produce the above effect. ATV also improved ferroptosis in I/R rat myocardium through the SMAD7/hepcidin pathway. Conclusions. ATV reversed the decline in H9C2 cell viability, mitochondrial shrinkage, and ROS elevation, and improved the myocardium ferroptosis through the SMAD7/hepcidin pathway in I/R rat.

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Section: Discussionmentioning

confidence: 99%

Atorvastatin Inhibits Ferroptosis of H9C2 Cells by regulatingSMAD7/Hepcidin Expression to Improve Ischemia-Reperfusion Injury

Peng

Liao

Zhou

et al. 2022

Cardiology Research and Practice

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“…The analysis of the total plasma concentration of ATV and its five metabolites ( o ‐OH‐ATV, p ‐OH‐ATV, ATV‐lactone, o ‐OH‐ATV‐lactone, and p ‐OH‐ATV‐lactone) and the unbound plasma concentration of ATV were performed by ultraperformance liquid chromatography‐tandem mass spectrometry, 34 according to a previous method developed and validated by our research group. The method of analysis of the total plasma concentration of ATV and its 5 metabolites was linear in the range of 25–200 ng/mL plasma.…”

Section: Clinical Study and Methodsmentioning

confidence: 99%

Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin

Cestari

Oliveira

Souza

et al. 2020

Clinical Translational Sci

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The present study assessed the effect of systemic lupus erythematosus (SLE) activity, a chronic and inflammatory autoimmune disease, on the sinusoidal uptake transporter OATP1B1 using atorvastatin (ATV) as a probe drug. Fifteen healthy subjects, 13 patients with controlled SLE (SLEDAI 0–4), and 12 patients with uncontrolled SLE (SLEDAI from 6 to 15), all women, were investigated. Apparent total clearance of midazolam (MDZ), a marker of CYP3A4 activity, did not vary among the three investigated groups. The controlled and uncontrolled SLE groups showed higher plasma concentrations of MCP‐1 and TNF‐α, while the uncontrolled SLE group also showed higher plasma concentrations of IL‐10. The uncontrolled SLE group showed higher area under the curve (AUC) for ATV (60.47 (43.76–83.56) vs. 30.56 (22.69–41.15) ng⋅hour/mL) and its inactive metabolite ATV‐lactone (98.74 (74.31–131.20) vs. 49.21 (34.89–69.42) ng⋅hour/mL), and lower apparent total clearance (330.7 (239.30–457.00) vs. 654.5 (486.00–881.4) L/hour) and apparent volume of distribution (2,609 (1,607–4,234) vs. 7,159 (4,904–10,450) L), when compared to the healthy subjects group (geometric mean and 95% confidence interval). The pharmacokinetics of ATV and its metabolites did not differ between the healthy subject group and the patients with controlled SLE group. In conclusion, uncontrolled SLE increased the systemic exposure to both ATV and ATV‐lactone, inferring inhibition of OATP1B1 activity, once in vivo CYP3A4 activity assessed by oral clearance of MDZ was unaltered. The inflammatory state, not the disease itself, was responsible for the changes described in the uncontrolled SLE group as a consequence of inhibition of OATP1B1, because systemic exposure to ATV and its metabolites were not altered in patients with controlled SLE.

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“…. On the other hand, few studies used UPLC MS/MS method for the estimation of AT in the biological fluids and are also indexed inTable 2[55,56,65,71,74,81,87,91,94,95,100]. Similar to HPLV-UV methods, C18 analytical columns have been extensively used in LC-MS/MS assay as a stationary phase because their long alkyl chain provides more efficient separation of nonpolar compounds in MS/ MS detection…”

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confidence: 99%

A review on liquid chromatographic methods for the bioanalysis of atorvastatin

Wadhwa

Rana

2021

Futur J Pharm Sci

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Background The unsatisfied clinical need has encouraged the development and validation of bioanalytical procedures for the quantification of drugs in biological samples because the monitoring of drug concentrations helps in personalizing the patient’s pharmacotherapy, assessing the adherence to therapy, and is also extensively useful for pharmacokinetics and drug-drug interactions studies. Main Body The present review aimed to provide insightful information about the various liquid chromatographic methods developed till 2019 for the analysis and quantification of atorvastatin, its metabolites, and co-administered drugs in the various biological matrices like the serum, plasma, and urine with special emphasis on sample preparation techniques applied before chromatographic analysis along with different chromatographic conditions and their validation data. A total of 88 published papers that have used liquid chromatography techniques to quantify atorvastatin in biological fluids are included in the study. Out of the total reported liquid chromatographic methods, 34% used UV spectrophotometer as a detector, and 55% used MS/MS as a detector. Whereas 38% of them used protein precipitation procedure, 33% applied liquid-liquid extraction approach, and 12% employed solid-phase extraction technique for sample preparation. Conclusion In the last decade, numerous bioanalytical procedures have been developed for the quantification of atorvastatin in different biological samples using liquid chromatographic techniques. Moreover, advancement in technology developed several new and advanced sample preparation approaches like dispersive liquid-liquid extraction, microextraction by packed sorbent, which have high recovery rates than conventional procedures. Thus, the summarized review may be consulted as an informative tool to support the optimization of new bioanalytical methods for the quantification of atorvastatin.

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Simultaneous analysis of the total plasma concentration of atorvastatin and its five metabolites and the unbound plasma concentration of atorvastatin: Application in a clinical pharmacokinetic study of single oral dose

Cited by 5 publications

References 15 publications

Atorvastatin Inhibits Ferroptosis of H9C2 Cells by regulatingSMAD7/Hepcidin Expression to Improve Ischemia-Reperfusion Injury

Atorvastatin Inhibits Ferroptosis of H9C2 Cells by regulatingSMAD7/Hepcidin Expression to Improve Ischemia-Reperfusion Injury

Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin

A review on liquid chromatographic methods for the bioanalysis of atorvastatin

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