- Inhibition of Organic Anion Transporting Polypeptide 1B1 and 1B3 by Betulinic Acid: Effects of Pre-incubation and Albumin in the Media. [Journal Article]
- JPJ Pharm Sci 2018 Feb 17
- Betulinic acid (BA), a plant-derived pentacyclic triterpenoid, may interact with the members of the organic anion transporting polypeptide 1B subfamily. Here, we investigated the interactions of BA a...
Betulinic acid (BA), a plant-derived pentacyclic triterpenoid, may interact with the members of the organic anion transporting polypeptide 1B subfamily. Here, we investigated the interactions of BA and its analogs with OATP1B1/3 and rat Oatp1b2 in vitro and in vivo. BA inhibited the activity of OATP1B1/3 and rat Oatp1b2 in vitro. Systemic exposure of atorvastatin was substantially altered with the intravenous co-administration of BA (20 mg/kg). Pre-incubation (incubation with inhibitors, followed by washout) with BA led to a sustained inhibition of OATP1B3, which recovered rapidly in the media containing 10% fetal bovine serum. The addition of albumin to the media decreased intracellular concentrations of BA and expedited the recovery of OATP1B3 activity following pre-incubation. For asunaprevir and cyclosporin A (previously known to inhibit OATP1B3 upon pre-incubation), the addition of albumin to the media shortened recovery time with asunaprevir, but not with cyclosporin A. Overall, our results showed that BA inhibits OATP1B transporters in vitro and may incur hepatic transporter-mediated drug interactions in vivo. Our results identify BA as another OATP1B3 inhibitor with pre-incubation effect and suggest that the pre-incubation effect and its duration is impacted by altered equilibrium of inhibitors between intracellular and extracellular space (e.g. albumin in the media).
- Simvastatin reduces adrenal catecholamine secretion evoked by stimulation of cholinergic nicotinic and angiotensinergic AT1receptors. [Journal Article]
- APArch Pharm Res 2018 Feb 19
- We investigated the influence of simvastatin, a statin, on the secretion of catecholamines (CA) in rat adrenal glands, and clarified its action mechanism. Simvastatin suppressed acetylcholine (ACh)-e...
We investigated the influence of simvastatin, a statin, on the secretion of catecholamines (CA) in rat adrenal glands, and clarified its action mechanism. Simvastatin suppressed acetylcholine (ACh)-evoked CA release in a dose- and time-dependent fashion. In the presence of simvastatin, CA secretion evoked by 1.1-dimethyl-4-phenyl piperazinium iodide (DMPP), angiotensin II, high K+, veratridine, and Bay-K-8644 was time-dependently inhibited. However, in the simultaneous presence of simvastatin and Nω-nitro-L-arginine methyl ester hydrochloride, CA secretion evoked by angiotensin II and DMPP recovered to control levels. Adrenal NO release was increased by simvastatin-treatment. Simvastatin-inhibited CA secretion was not affected by treatment with mevalonate. Pravastatin did not influence ACh-evoked CA secretion, while atorvastatin reduced it. In the simultaneous presence of simvastatin and fimasartan, ACh-induced CA release was markedly reduced compared to that of fimasartan-treatment alone. We present the first evidence that simvastatin reduces adrenal CA secretion induced by stimulation of nicotinic and AT1-receptors. Simvastatin-induced inhibition seems to involve reducing the influx of both Ca2+and Na+into adrenochromaffin cells, partly via the elevation of NO production by NO synthase activation, without inhibition of 3-hydroxy-methylglutaryl coenzyme A reductase. Co-administration of simvastatin and fimasartan may be clinically helpful for the treatment of cardiovascular diseases.
- Prehospital Events in ST- Elevation Myocardial Infarction Undergoing Primary Angioplasty. [Journal Article]
- JJJNMA J Nepal Med Assoc 2017 Oct-Dec; 56(208):421-425
- CONCLUSIONS: Chest pain was common in morning and the prehospital delay can be minimized by improving time from symptom to first medical contact and first medical contact to Emergency room.
- In vitro and in vivo evaluation of cyclodextrin-based nanosponges for enhancing oral bioavailability of atorvastatin calcium. [Journal Article]
- DDDrug Dev Ind Pharm 2018 Feb 16; :1-34
- The aim of this study was to explore the feasibility of complexing the poorly water-soluble drug atorvastatin calcium (AC) with β-cyclodextrin (β-CD) based nanosponges (NS), which offer advantages of...
The aim of this study was to explore the feasibility of complexing the poorly water-soluble drug atorvastatin calcium (AC) with β-cyclodextrin (β-CD) based nanosponges (NS), which offer advantages of improving dissolution rate and eventually oral bioavailability. Blank NS were fabricated at first by reacting β-CD with the cross-linker carbonyldiimidazole at different molar ratios (1:2, 1:4 and 1:8), then NS of highest solubilization extent for AC were complexed with AC. AC loaded NS (AC-NS) were characterized for various physicochemical properties. Pharmacokinetic, pharmacodynamic and histological finding of AC-NS were performed in rats. The prepared AC-NS showed particles size ranged from 408.7±12.9 to 423 ±15.9 nm while zeta potential values varied from -21.7±0.90 to -22.7±0.85 mV. The loading capacity varied from 17.9±1.21 to 34.1±1.16%. DSC, FT-IR and PXRD studies confirmed the complexation of AC with NS and amorphous state of the drug in the complex. AC-NS displayed a biphasic release pattern with increase in the dissolution rate of AC as compared to plain AC. Oral administration of AC-NS (1:4 w/w, drug: NS) to rats led to 2.13-folds increase in the bioavailability as compared to AC suspension. Pharmacodynamic studies in rats with fatty liver revealed significant reduction (P < 0.05) in total cholesterol, triglyceride, LDL-C and increased level of beneficial HDL-C along with improvement in the associated liver steatosis as confirmed through photomicrographs of liver sections. In this study, we confirmed that complexation of AC with NS would be a viable approach for improving oral bioavailability and in vivo performance of AC.
- The effect of high-dose atorvastatin on neural activity and cognitive function. [Journal Article]
- AHAm Heart J 2018; 197:166-174
- CONCLUSIONS: Six months of high dose atorvastatin therapy is not associated with measurable changes in neuropsychological test scores, but did evoke transient differences in brain activation patterns. Larger, longer-term clinical trials are necessary to confirm these findings and evaluate their clinical implications.
- Cognition and brain changes associated with high-dose atorvastatin: A BOLD proposition? [Editorial]
- AHAm Heart J 2018; 197:163-165
- The Effect of Intensive Statin Therapy on Symptomatic Intracranial Arterial Stenosis. [Journal Article]
- IJIran J Public Health 2018; 47(2):231-236
- CONCLUSIONS: Atorvastatin at 40 mg/d has a significant advantage compared with atorvastatin at 20 mg/d and 10 mg/d in reducing cerebrovascular events and improving cerebral blood flow.
- Incidence of statin-drug interactions in Croatian community pharmacy. [Journal Article]
- PPharmazie 2017 Mar 01; 72(3):187-191
- Statins are among the most frequently issued drugs that patients usually need to take for a lifetime. They are often an integral part of a polytherapeutic approach in preventing and treating cardiova...
Statins are among the most frequently issued drugs that patients usually need to take for a lifetime. They are often an integral part of a polytherapeutic approach in preventing and treating cardiovascular diseases. As such, they might often interact with drugs prescribed for treating acute and chronic conditions. A pharmacist is the final professional control before a drug reaches the patient and his role in preventing drug-drug interactions is crucial. The objective of this research was to analyse the incidence and relevance of potential drug interactions with statins in community pharmacy. We retrospectively analysed the prescribed pharmacotherapy of 153 patients who were taking statins. Lexicomp® Lexi-Interact™ Online (Lexi-Comp, Inc., Hudson, USA) was used to identify interactions. The mean age of study patients was 65.5 (52.3% women). The most frequently used statin was atorvastatin and the least used was fluvastatin. The average number of coprescribed drugs was 4. The highest number of interactions which required enhanced patient surveillance were registered with atorvastatin, while interactions which might need specific therapy modification were mostly seen with simvastatin. Systematic and regular control of potential clinically significant drug-drug interactions in the prescribed pharmacotherapy is important for therapy outcomes and appropriate pharmaceutical surveillance in issuing pharmacotherapy.
- The effect ofSLCO1B1polymorphism on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in healthy Chinese people. [Journal Article]
- PPharmazie 2017 Jun 01; 72(6):365-368
- The pharmacokinetics of statins show substantial inter-subject variability. Increasing systemic exposure of statins may lead to adverse drug reactions such as myopathy. The variation in statin pharma...
The pharmacokinetics of statins show substantial inter-subject variability. Increasing systemic exposure of statins may lead to adverse drug reactions such as myopathy. The variation in statin pharmacokinetics is partly explained by genetic factors. OATP1B1, coded by SLCO1B1 transports a large number of therapeutic drugs, such as atorvastatin. Here we investigated the effect of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and its metabolites. Two pharmacokinetic studies were conducted in Chinese Han volunteers and 132 volunteers were enrolled in our study as 72 in trial 1 and 60 in trial 2. A LC-MS/MS method was developed for the identification and quantification of atorvastatin acid and its metabolites. S LCO1B1 c.521T>C (rs4149056) was identified by the MALDI-TOF MS and Sequenom MassARRAY system. The distribution frequencies of SLCO1B1 c.521T>C were in agreement with Hardy-Weinberg equilibrium both in trial 1 and trial 2. In subjects with 521C allele the mean Cmax, AUC0-24h and AUC0-∞ of atorvastatin acid and 2-hydroxyatorvastatin acid were significantly higher than subjects with 521TT genotype, while the mean CL was lower. In conclusion, our results suggested that SLCO1B1 c.521T>C had an effect on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in Chinese Han population. Subjects with 521C allele have an increased risk of toxic effects caused by atorvastatin.
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- Influence ofSLCO1B1polymorphisms on atorvastatin efficacy and safety in Macedonian subjects. [Journal Article]
- PPharmazie 2017 May 01; 72(5):288-295
- Atorvastatin, as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is a widely prescribed medication for the treatment of dyslipidemia. However, despite its clinical efficacy in re...
Atorvastatin, as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is a widely prescribed medication for the treatment of dyslipidemia. However, despite its clinical efficacy in reducing major cardiovascular events, a wide inter-individual variability in its response exists. Several studies in this area point to the effect of polymorphisms in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene encoding the multiple organic anion-transporting polypeptide 1B1 (OATP1B1) involved in hepatic uptake of atorvastatin. Hence, the aim of this study was to analyze the association between the SLCO1B1 c.388A>G, c.521T>C, c.571T>C, c.597C>T, c.1086C>T, c.1463G>C and c.*439T>G polymorphisms and lipid-lowering effect and safety of atorvastatin. A hundred and fifty six patients with hyperlipidemia IIa and IIb, all of Macedonian origin, were included in the study receiving atorvastatin 20 - 80 mg/day for 3 months. SLCO1B1 single nucleotide polymorphisms (SNPs) were genotyped using the TaqMan allelic discrimination assay. As parameters of atorvastatin response, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein A (ApoAI), apolipoprotein B (ApoB), lipoprotein(a) (Lp(a)), creatine phosphokinase (CPK), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured, using standard laboratory methods, at baseline and after 3 months of treatment. No statistically significant association between the different SLCO1B1 SNPs and atorvastatin response was observed. However, the carriers of c.521CC manifested a lower decrease in plasma levels of TG, TC, LDL-C and Lp(a), with percentage difference being 16%, 7%, 29% and 149%, respectively, compared to the carriers of c.521TT variant. Lower increase in HDL-C (271%) and ApoAI (293%) and higher increase in CPK (69%) in c.521CC carriers were also observed, confirming the lower OATP1B1 activity in carriers of the variant c.521 C allele. Similar results were obtained when a comparison between the percentage of biochemical parameter change was made between *15/*16/*17 heterozygotes and *15/*16/*17 non-carriers. The lack of a statistically significant association between the SLCO1B1 polymorphism and atorvastatin response can be explained dominantly by the low number of individuals homozygous for the rare c.521C variant allele. Despite this limitation, the study offers valuable information on the influence of the genetic determinant SLCO1B1 on atorvastatin response in the Macedonian population.