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Pharmaceutical Biology Dec 2022Patients with non-alcoholic steatohepatitis (NASH) may have a simultaneous intake of pravastatin and evodiamine-containing herbs.
CONTEXT
Patients with non-alcoholic steatohepatitis (NASH) may have a simultaneous intake of pravastatin and evodiamine-containing herbs.
OBJECTIVE
The effect of evodiamine on the pharmacokinetics of pravastatin and its potential mechanisms were investigated in NASH rats.
MATERIALS AND METHODS
The NASH model was conducted with feeding a methionine choline-deficient (MCD) diet for 8 weeks. Sprague-Dawley rats were randomised equally ( = 6) into NASH group, evodiamine group (10 mg/kg), pravastatin group (10 mg/kg), and evodiamine (10 mg/kg) + pravastatin (10 mg/kg) group. Normal control rats were fed a standard diet. Effects of evodiamine on the pharmacokinetics, distribution, and uptake of pravastatin were investigated.
RESULTS
Evodiamine decreased (159.43 ± 26.63 vs. 125.61 ± 22.17 μg/L), AUC (18.17 ± 2.52 vs. 14.91 ± 2.03 mg/min/L) and AUC (22.99 ± 2.62 vs. 19.50 ± 2.31 mg/min/L) of orally administered pravastatin in NASH rats, but had no significant effect in normal rats. Evodiamine enhanced the uptake (from 154.85 ± 23.17 to 198.48 ± 26.31 pmol/mg protein) and distribution (from 736.61 ± 108.07 to 911.89 ± 124.64 ng/g tissue) of pravastatin in NASH rat liver. The expression of Oatp1a1, Oatp1a4, and Oatp1b2 was up-regulated 1.48-, 1.38-, and 1.51-fold by evodiamine. Evodiamine decreased the levels of IL-1β, IL-6, and TNF-α by 27.82%, 24.76%, and 29.72% in NASH rats, respectively.
DISCUSSION AND CONCLUSIONS
Evodiamine decreased the systemic exposure of pravastatin by up-regulating the expression of OATPs. These results provide a reference for further validation of this interaction in humans.
Topics: Animals; Area Under Curve; Herb-Drug Interactions; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Non-alcoholic Fatty Liver Disease; Organic Anion Transporters; Pravastatin; Quinazolines; Rats; Rats, Sprague-Dawley; Up-Regulation
PubMed: 35171063
DOI: 10.1080/13880209.2022.2036767 -
Journal of Diabetes Jun 2024Pravastatin is an oral lipid-lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but...
BACKGROUND
Pravastatin is an oral lipid-lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but the mechanism is unclear.
METHODS
In this study, 16S rRNA sequencing and qRT-PCR wereused to detect the differential gut bacteria. Metabolomics and ELISA were used to analyze the differential metabolites. qRT-PCR and western blotting (WB) were used to detect genes expression. Flow cytometry was used to analyze macrophage phenotype. Immunohistochemistry was used to analyze aortic calcification.
RESULTS
We found that gut Bacteroides fragilis (BF) increased significantly in patients who took pravastatin or type 2 diabetes (T2D) mice treated with pravastatin. In vitro experiments showed that pravastatin had little effect on BF but significantly promoted BF proliferation in vivo. Further analysis showed that ArsR was an important gene for pravastatin to regulate the activation of BF, and overexpression of ArsR significantly promoted the secretion of 3,4,5-trimethoxycinnamic acid (TMCA). Importantly, pravastatin significantly promoted BF secretion of TMCA and significantly increased TMCA secretion in T2D patients or T2D mice. TMCA had little effect on vascular smooth muscle cell calcification but significantly promoted macrophage M1 polarization, which we had demonstrated that M1 macrophages promoted T2D VC. In vivo studies found that pravastatin significantly upregulated TMCA levels in the feces and serum of T2D mice transplanted with BF and promoted the macrophage M1 polarization in bone marrow and the osteoblastic differentiation of aortic cells. Similar results were obtained in T2D mice after intravenous infusion of TMCA.
CONCLUSIONS
Promoting intestinal BF to secrete TMCA, which leads to macrophage M1 polarization, is an important mechanism by which pravastatin promotes calcification, and the result will be used for the optimization of clinical medication strategies of pravastatin supplying a theoretical basis and experimental basis.
Topics: Pravastatin; Animals; Vascular Calcification; Mice; Macrophages; Humans; Diabetes Mellitus, Type 2; Bacteroides fragilis; Male; Gastrointestinal Microbiome; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice, Inbred C57BL; Female
PubMed: 38112268
DOI: 10.1111/1753-0407.13514 -
Biochemical Pharmacology Apr 2020The downregulation of hepatic uptake transporters, including those of the OATP family, are a well known consequence of nonalcoholic steatohepatitis (NASH). Prior studies...
The downregulation of hepatic uptake transporters, including those of the OATP family, are a well known consequence of nonalcoholic steatohepatitis (NASH). Prior studies have shown that the combination of NASH and Oatp1b2 knockout synergistically reduces the clearance of pravastatin (PRAV) in the methionine and choline deficient (MCD) mouse model of NASH, and the current study therefore aimed to determine the impact of NASH and genetic heterozygosity of Oatp1b2 on PRAV clearance, modeling the overlap between the 24% of the human population who are heterozygous for non-functioning OATP1B1, and the ~15% with NASH, potentially placing these people at higher risk of statin-induced myopathy. Therefore, male C57BL/6 wild-type (WT), Oatp1b2+/- (HET), and Oatp1b2-/- (KO) mice were fed either a control (methionine and choline sufficient) or methionine and choline-deficient (MCD) diet to induce NASH. After six weeks of feeding, pravastatin was administered via the carotid artery. Blood and bile samples were collected throughout 90 min after PRAV administration. The concentration of PRAV in plasma, bile, liver, kidney, and muscle was determined by liquid chromatography-tandem mass spectrometry. MCD diet did not alter the plasma AUC values of PRAV in either WT or HET mice. However, the MCD diet increased plasma AUC by 4.4-fold in KO mice. MCD diet and nonfunctional Oatp1b2 synergistically increased not only plasma AUC but also the extrahepatic tissue concentration of pravastatin, whereas the partially decreased function of Oatp1b2 and NASH together were insufficient in significantly altering PRAV pharmacokinetics. These data suggest that a single copy of fully functional OATP1B1 in NASH patients may be sufficient to avoid the increase of pravastatin toxicity.
Topics: Animals; Disease Models, Animal; Gene Dosage; Gene Expression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver-Specific Organic Anion Transporter 1; Metabolic Clearance Rate; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Pravastatin
PubMed: 31881192
DOI: 10.1016/j.bcp.2019.113780 -
Current Medicinal Chemistry 2016Non-cholesterol sterols have been used as markers of cholesterol intestinal absorption and hepatic synthesis, leading to a better understanding of cholesterol... (Review)
Review
Non-cholesterol sterols have been used as markers of cholesterol intestinal absorption and hepatic synthesis, leading to a better understanding of cholesterol homeostasis in humans. This review discusses the main noncholesterol sterols that are clinically useful, different methods to quantify the factors associated with blood concentration, and the potential role of non-cholesterol sterols in the diagnosis and treatment of different types of dyslipidemia. The main indication is the use of non-cholesterol sterols for the diagnosis of rare diseases associated with defects in cholesterol synthesis or anomalies in the absorption and/or elimination of phytosterols. However, other potential uses, including the diagnosis of certain hypercholesterolemias and the individualization of lipid-lowering therapies, are promising as they could help treat a wider population.
Topics: Bile Acids and Salts; Cholesterol; Dyslipidemias; Ezetimibe; Humans; Membrane Proteins; Membrane Transport Proteins; Oxysterols; Phytosterols; Pravastatin; Sterols
PubMed: 27142287
DOI: 10.2174/0929867323666160504104133 -
Journal of Thoracic Oncology : Official... Aug 2023To determine the effect of statin use during concurrent chemoradiotherapy (CCRT) on overall survival and esophageal squamous cell carcinoma (ESCC)-specific survival in...
INTRODUCTION
To determine the effect of statin use during concurrent chemoradiotherapy (CCRT) on overall survival and esophageal squamous cell carcinoma (ESCC)-specific survival in patients with ESCC receiving standard CCRT.
METHODS
In this propensity score-matching cohort study, we used data from the Taiwan Cancer Registry Database and National Health Insurance Research Database to investigate the effects of statin use during the period of CCRT on overall survival and ESCC-specific survival.
RESULTS
Statin use during the period of CCRT was found to be a considerable and independent prognostic factor for overall survival and ESCC-specific survival. The adjusted hazard ratio (aHR) for all-cause mortality in the statin group compared with that of the non-statin group was 0.65 (95% confidence interval: 0.51-0.84, p = 0.0009). The aHR for ESCC-specific mortality in the statin group compared with that of the non-statin group was 0.63 (95% confidence interval: 0.47-0.84, p = 0.0016). The use of hydrophilic statins such as rosuvastatin and pravastatin was associated with the greatest survival benefits. A dose-response relationship was also found, with higher cumulative defined daily doses and higher daily intensity of statin use associated with lower mortality.
CONCLUSIONS
This study is the first to reveal that statin use during the period of CCRT for ESCC is associated with improvement in overall survival and ESCC-specific survival. In addition, we found that use of rosuvastatin, pravastatin, and simvastatin was associated with better survival outcomes for patients with ESCC receiving CCRT. Furthermore, we found a dose-response relationship of statin use associated with lower ESCC-specific mortality.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Carcinoma, Squamous Cell; Esophageal Neoplasms; Cohort Studies; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Propensity Score; Rosuvastatin Calcium; Pravastatin; Lung Neoplasms; Chemoradiotherapy
PubMed: 37085031
DOI: 10.1016/j.jtho.2023.04.005 -
Frontiers in Pharmacology 2022This study aimed to determine the effect of vitamin D (VD) deficiency on the efficacy and pharmacokinetics of pravastatin and clarify whether the effects are mediated by...
This study aimed to determine the effect of vitamin D (VD) deficiency on the efficacy and pharmacokinetics of pravastatin and clarify whether the effects are mediated by Organic anion-transporting polypeptides (OATPs). Experiments were conducted in rats to explore the effect of VD deficiency on the pharmacodynamics and pharmacokinetics of pravastatin. In the pharmacodynamic study, rats were fed a VD-free or VD-supplement high-fat diet for 25-30 days, and plasma 25(OH)VD was dynamically monitored. The response of pravastatin (changes in blood lipids) on rats were then examined after 15 days of pravastatin treatment. In the pharmacokinetic study, rats were fed a VD-free or VD-supplement diet for 25-30 days. The pharmacokinetics of single oral dose pravastatin was then studied, and intestinal and hepatic Oatp1a1 and Oatp2b1 expression was determined using quantitative polymerase chain reaction (qPCR) and western blot. Furthermore, OATP1B1 and OATP2B1 expression in Huh7 cells with or without 1.25(OH)D were assessed via qPCR and western blot. For the pharmacodynamic study, the decrease of total cholesterol and increase of high-density lipoprotein cholesterol in VD-deficient rats were smaller than in VD-sufficient rats, indicating that VD deficiency reduced the response of pravastatin in rats. For the pharmacokinetic study, the plasma exposure slightly increased, and liver exposure decreased in VD-deficient rats, but not significantly. VD deficiency decreased the Oatp1a1 and Oatp2b1 expression in the liver, but not in the small intestine. Similarly, OATP1B1 and OATP2B1 protein levels in Huh7 cells were reduced when 1.25(OH)D was absent. In conclusion, VD deficiency can decrease the response of pravastatin in rats by reducing the liver pravastatin exposure and expression of hepatic OATPs, consistent with the extended hepatic clearance model theory.
PubMed: 35250587
DOI: 10.3389/fphar.2022.841954 -
Die Pharmazie May 2022Various chemical reagents containing inhibitors of mitochondrial activity, antioxidants, nuclear factor-kappa B (NF-kB) inhibitor, mammalian target of rapamycin (mTOR)...
Various chemical reagents containing inhibitors of mitochondrial activity, antioxidants, nuclear factor-kappa B (NF-kB) inhibitor, mammalian target of rapamycin (mTOR) inhibitor and other clinical therapeutics were screened in order to identify those that selectively decrease the viability of senescent human lung fibroblasts. Cell viability was measured using the CCK-8 assay. The results showed that pravastatin, a drug for hyperlipidemia, decreased the viability of senescent cells but not non-senescent cells. The effect of pravastatin on senescent cells is thought to be due to the inhibition of cell proliferation, rather than cell death. The effect of pravastatin was further investigated using the glucose metabolism assay, which showed that glucose consumption was inhibited both in non-senescent and senescent cells and intracellular nicotinamide adenine dinucleotide (NAD) was decreased in senescent cells. Changes to the mRNA expression levels of senescence-associated genes in response to pravastatin treatment were quantified by real-time-qPCR. There were no significant changes in the relative mRNA expression levels of IL-1β, p16, p21, and p53 in pravastatin-treated non-senescent cells, whereas the expression of IL-1β and p16 were increased by pravastatin only in senescent cells. The results of this study suggest that pravastatin does not induce senolysis, but rather selectively inhibits the proliferation of senescent cells and that cellular senescence is enhanced by decreasing intracellular NAD and promoting IL-1β production.
Topics: Fibroblasts; Humans; Lung; NAD; Pravastatin; RNA, Messenger
PubMed: 35655385
DOI: 10.1691/ph.2022.2327 -
Experimental Lung Research 2019Obesity is one of the factors associated with severe, uncontrolled asthma. The effect of pravastatin on asthmatic airway inflammation in obesity has not been evaluated....
Obesity is one of the factors associated with severe, uncontrolled asthma. The effect of pravastatin on asthmatic airway inflammation in obesity has not been evaluated. C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity with or without ovalbumin (OVA) sensitization and challenge. Pravastatin was administered intraperitoneally during the OVA treatment. Airway inflammation and airway hyper-responsiveness (AHR) were analyzed and lung tissues were examined. The changes in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were measured in the lung tissues. HFD with OVA sensitization and challenge exacerbated eosinophilic and neutrophilic airway inflammation and increased AHR compared to lean asthma mice. The levels of cytokines examined in bronchoalveolar lavage fluid (BALF) revealed that the expressions of IL-4, 5, and 17 were elevated in the obese asthmatic group and decreased after pravastatin treatment, indicating that both the Th2 and Th17 pathways were stimulated by HFD-induced obesity and OVA challenge and suppressed by pravastatin treatment. Moreover, the serum leptin and adiponectin ratio was elevated only in obese asthmatic mice and decreased with pravastatin administration. Pravastatin successfully alleviated the airway inflammation of lung tissues and AHR in both obese and lean asthmatic mice, however, treatment with pravastatin had no effects on BALF cell counts and cytokines in lean asthma mice. In lung tissues, the phosphorylation of p38 MAPK was significantly decreased in lean as well as obese asthmatic mice. Pravastatin treatment in obese asthmatic mice suppressed allergic airway infiltration and AHR by inhibition of Th2 and Th17-associated signaling pathways, decreasing the leptin expression and downstream p38 MAPK signaling pathways. The effect on lean asthmatic mice was different, independent of airway cell counts and cytokines.
Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Female; Inflammation; Lung; Mice; Mice, Inbred C57BL; Obesity; Ovalbumin; Phosphatidylinositol 3-Kinases; Pravastatin; Respiratory Hypersensitivity; Th17 Cells; Th2 Cells
PubMed: 31608695
DOI: 10.1080/01902148.2019.1675807 -
Biomedical Chromatography : BMC Apr 2016This report describes the development and validation of a chromatography/tandem mass spectrometry method for the quantitative determination of pravastatin and its... (Clinical Trial)
Clinical Trial
This report describes the development and validation of a chromatography/tandem mass spectrometry method for the quantitative determination of pravastatin and its metabolite (3α-hydroxy pravastatin) in plasma and urine of pregnant patients under treatment with pravastatin, as part of a clinical trial. The method includes a one-step sample preparation by liquid-liquid extraction. The extraction recovery of the analytes ranged between 93.8 and 99.5% in plasma. The lower limits of quantitation of the analytes in plasma samples were 0.106 ng/mL for pravastatin and 0.105 ng/mL for 3α-hydroxy pravastatin, while in urine samples they were 19.7 ng/mL for pravastatin and 2.00 ng/mL for 3α-hydroxy pravastatin. The relative deviation of this method was <10% for intra- and interday assays in plasma and urine samples, and the accuracy ranged between 97.2 and 106% in plasma, and between 98.2 and 105% in urine. The method described in this report was successfully utilized for determining the pharmacokinetics of pravastatin in pregnant patients enrolled in a pilot clinical trial for prevention of preeclampsia.
Topics: Anticholesteremic Agents; Chromatography, High Pressure Liquid; Female; Humans; Limit of Detection; Liquid-Liquid Extraction; Pravastatin; Pregnancy; Tandem Mass Spectrometry
PubMed: 26360932
DOI: 10.1002/bmc.3581 -
International Journal of Pharmaceutics Dec 2015Wiechers' programme "Formulating for Efficacy" initiated a new strategy to optimise the oil phase of topical formulations in order to achieve optimal transdermal drug...
Wiechers' programme "Formulating for Efficacy" initiated a new strategy to optimise the oil phase of topical formulations in order to achieve optimal transdermal drug delivery. This new approach uses the "Delivery Gap Theory" on any active pharmaceutical ingredients (APIs) to test if it could enhance transdermal drug delivery. The aim of the study was to formulate six different semi-solid formulations (three creams and three emulgels) with 2% pravastatin as the API in order to investigate the "Delivery Gap Principle", by determining which formulation would deliver pravastatin best to the target-site (system circulation). The three cream- and three emulgel formulations had different polarities, i.e. a formulation with polarity equal to that of the stratum corneum (optimised), a non-polar (lipophilic)- and a polar (hydrophilic)-formulation. Franz cell diffusion studies were executed over 12h and the optimised emulgel (2.578μg/cm(2)) had the highest median amount per area obtained. Tape stripping followed the diffusion studies and in the stratum corneum-epidermis, the hydrophilic emulgel (1.448μg/ml) contained the highest median pravastatin concentration and the epidermis-dermis the optimised emulgel (0.849μg/ml) depicted the highest pravastatin concentration. During this study, it was observed that when both emulgel and cream formulations were compared; the emulgels enhanced the delivery of pravastatin more than the creams.
Topics: Administration, Cutaneous; Chemistry, Pharmaceutical; Diffusion; Ointments; Pravastatin
PubMed: 26505148
DOI: 10.1016/j.ijpharm.2015.10.034