QT time prolongation
Adverse drug events
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Atorvastatin is used as primary and secondary prophylaxis for high cholesterol and triglyceride levels to prevent cardiovascular events such as heart attack or stroke. It is taken orally as a tablet. Atorvastatin is one of the HMG-CoA reductase inhibitors. This enzyme in the liver is needed to produce the body's own cholesterol. When it is blocked, the level of LDL cholesterol in the blood decreases. In addition, there are pleiotropic (multiple) effects that protect the blood vessel walls and thus also lower the risk of a cardiovascular event.
The warnings are checked for the combination of several active substances. For the individual substances, please consult the relevant specialist information.
|Atorvastatin||1 [1,5.06] 1,2|
Since only atorvastatin was entered without any further substances, no pharmacokinetic interactions can be detected.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Atorvastatin has a low oral bioavailability [ F ] of 14%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is 14 hours and constant plasma levels [ Css ] are reached after approximately 56 hours. The protein binding [ Pb ] is very strong at 98.5% and the volume of distribution [ Vd ] is very large at 381 liters. However, since the substance has a high hepatic extraction rate of 0.73, only changes in the liver blood flow [Q] are relevant. About 21.4% of an administered dose is excreted unchanged via the kidneys and this proportion is seldom changed by interactions. The metabolism mainly takes place via CYP3A4 and the active transport takes place partly via BCRP, MRP2, MRP4, OATP1A2, OATP1B1, OATP1B3, OATP2B1 and PGP.
|Serotonergic Effects a||0||Ø|
Rating: According to our knowledge, atorvastatin does not increase serotonergic activity.
|Kiesel & Durán b||0||Ø|
Rating: According to our findings, atorvastatin does not increase anticholinergic activity.
QT time prolongation
We do not know of any QT-prolonging potential for atorvastatin.
General adverse effects
|Side effects||∑ frequency||ato|
|Urinary tract infection||8.0 %||8.0|
|Intracranial hemorrhage||2.3 %||2.3|
|Elevated transaminases||0.8 %||0.8|
|Elevated creatine kinase||0.4 %||0.4|
Liver failure: atorvastatin
Allergic skin reactions like pruritus and rash: atorvastatin
Rupture of tendon: atorvastatin
Based on your
Abstract: The objective of this study was to determine the effects of renal dysfunction on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Nineteen subjects with calculated creatinine clearances ranging from 13 mL/min to 143 mL/min were administered 10 mg atorvastatin daily for 2 weeks. Pharmacokinetic parameters and lipid responses were analyzed by regression on calculated creatinine clearance. Correlations between steady-state atorvastatin pharmacokinetic or pharmacodynamic parameters and creatinine clearance were weak and, in general, did not achieve statistical significance. Although the elimination rate constant, lambda z (0.579), was significantly correlated with creatinine clearance, neither maximum plasma concentration (Cmax, -0.361) nor oral clearance (Cl/F, 0.306) were; thus, steady-state exposure is not altered. Renal impairment has no significant effect on pharmacodynamics and pharmacokinetics of atorvastatin.
Abstract: BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are metabolized by distinct pathways that may alter the extent of drug-drug interactions. Cerivastatin is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8. Atorvastatin is metabolized solely by CYP3A4, and pravastatin metabolism is not well defined. Coadministration of higher doses of these statins with CYP3A4 inhibitors has the potential for eliciting adverse drug-drug interactions. OBJECTIVE: To determine the comparative effect of itraconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of cerivastatin, atorvastatin, and pravastatin. METHODS: In this single-site, randomized, three-way crossover, open-labeled study, healthy subjects (n = 18) received single doses of cerivastatin 0.8 mg, atorvastatin 20 mg, or pravastatin 40 mg without and with itraconazole 200 mg. Pharmacokinetic parameters [AUC(0-infinity), AUC(0-tn), peak concentration (Cmax), time to reach Cmax (tmax), and half-life (t1/2)] were determined for parent statins and major metabolites. RESULTS: Concomitant cerivastatin/itraconazole treatment produced small elevations in the cerivastatin AUC(0-infinity), Cmax, and t1/2 (27%, 25%, and 19%, respectively; P < .05 versus cerivastatin alone). Itraconazole coadministration produced similar changes in pravastatin pharmacokinetics [AUC elevated 51% (P < .05 versus pravastatin alone), 24% (Cmax), and 23% (t1/2), respectively]. However, itraconazole dramatically increased atorvastatin AUC (150%), Cmax (38%), and t1/2 (30%) (P < .05). The elevation in atorvastatin AUC was significantly greater than that of cerivastatin (P < .005) or pravastatin (P < .005). CONCLUSION: Itraconazole markedly elevated atorvastatin plasma levels (2.5-fold) after 20 mg dosing, suggesting that concomitant itraconazole/atorvastatin therapy be carefully considered. Itraconazole produced modest elevations in the plasma levels of cerivastatin 0.8 mg or pravastatin 40 mg (1.3-fold and 1.5-fold, respectively), indicating that combination treatment with itraconazole with cerivastatin or pravastatin may be preferable.
Abstract: Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease. Atorvastatin lowers plasma low-density lipoprotein (LDL) cholesterol levels by inhibition of HMG-CoA reductase. The mean dose-response relationship has been shown to be log-linear for atorvastatin, but plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose. The clinical dosage range for atorvastatin is 10-80 mg/day, and it is given in the acid form. Atorvastatin acid is highly soluble and permeable, and the drug is completely absorbed after oral administration. However, atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The volume of distribution of atorvastatin acid is 381L, and plasma protein binding exceeds 98%. Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine. In vitro, atorvastatin acid is a substrate for P-glycoprotein, organic anion-transporting polypeptide (OATP) C and H+-monocarboxylic acid cotransporter. The total plasma clearance of atorvastatin acid is 625 mL/min and the half-life is about 7 hours. The renal route is of minor importance (<1%) for the elimination of atorvastatin acid. In vivo, cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the acid and the lactone forms of atorvastatin. Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3. Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of atorvastatin acid after oral administration, as indicated by decreased peak concentration and increased time to peak concentration. Women appear to have a slightly lower plasma exposure to atorvastatin for a given dose. Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by OATP C and P-glycoprotein, and drug-drug interactions with potent inhibitors of these systems, such as itraconazole, nelfinavir, ritonavir, cyclosporin, fibrates, erythromycin and grapefruit juice, have been demonstrated. An interaction with gemfibrozil seems to be mediated by inhibition of glucuronidation. A few case studies have reported rhabdomyolysis when the pharmacokinetics of atorvastatin have been affected by interacting drugs. Atorvastatin increases the bioavailability of digoxin, most probably by inhibition of P-glycoprotein, but does not affect the pharmacokinetics of ritonavir, nelfinavir or terfenadine.
Abstract: BACKGROUND: The cardiac effects of statins are subject to controversial discussion, and the mechanism of their uptake into the human heart is unknown. A candidate protein is the organic anion transporting polypeptide (OATP) 2B1 (SLCO2B1), because related transporters are involved in the uptake of statins into the human liver. In this study we examine OATP2B1 expression in the human heart and describe statins as inhibitors and substrates of OATP2B1. METHODS: The expression of OATP2B1 was analyzed in 46 human atrial and 15 ventricular samples, including samples from hearts with dilated cardiomyopathy and hearts with ischemic cardiomyopathy. RESULTS: Significant messenger ribonucleic acid expression was found in all samples, with no difference in the diseased hearts. However, patients who had taken atorvastatin exhibit decreased OATP2B1 messenger ribonucleic acid expression compared with patients with no statin treatment. OATP2B1 protein was detected at approximately 85 kd in atrial samples, as well as ventricular samples, and could be localized to the vascular endothelium. Furthermore, estrone-3-sulfate transport into OATP2B1-overexpressing Madin-Darby canine kidney II cells was inhibited by various drugs, including atorvastatin, simvastatin, cerivastatin, glyburide (INN, glibenclamide), and gemfibrozil, with the most pronounced effect being found for atorvastatin (inhibition constant, 0.7 +/- 0.4 micromol/L). Whereas simvastatin (lactone) itself was not transported by OATP2B1, atorvastatin was identified as a high-affinity substrate for OATP2B1 (Michaelis-Menten constant, 0.2 micromol/L) by direct transport measurement via liquid chromatography-tandem mass spectrometry. CONCLUSION: OATP2B1 is a high-affinity uptake transporter for atorvastatin and is expressed in the vascular endothelium of the human heart, suggesting its involvement in cardiac uptake of atorvastatin.
Abstract: The inhibition of hepatic uptake transporters, such as OATP1B1, on the pharmacokinetics of atorvastatin is unknown. Here, we investigate the effect of a model hepatic transporter inhibitor, rifampin, on the kinetics of atorvastatin and its metabolites in humans. The inhibitory effect of a single rifampin dose on atorvastatin kinetics was studied in 11 healthy volunteers in a randomized, crossover study. Each subject received two 40-mg doses of atorvastatin, one on study day 1 and one on study day 8, separated by 1 week. One intravenous 30-min infusion of 600 mg rifampin was administered to each subject on either study day 1 or study day 8. Plasma concentrations of atorvastatin and metabolites were above the limits of quantitation for up to 24 h after dosing. Rifampin significantly increased the total area under the plasma concentration-time curve (AUC) of atorvastatin acid by 6.8+/-2.4-fold and that of 2-hydroxy-atorvastatin acid and 4-hydroxy-atorvastatin acid by 6.8+/-2.5- and 3.9+/-2.4-fold, respectively. The AUC values of the lactone forms of atorvastatin, 2-hydroxy-atorvastatin and 4-hydroxy-atorvastatin, were also significantly increased, but to a lower extent. An intravenous dose of rifampin substantially increased the plasma concentrations of atorvastatin and its acid and lactone metabolites. The data confirm that OATP1B transporters represent the major hepatic uptake systems for atorvastatin and its active metabolites. Inhibition of hepatic uptake may have consequences for efficacy and toxicity of drugs like atorvastatin that are mainly eliminated by the hepatobiliary system.
Abstract: Thirty-two healthy volunteers with different SLCO1B1 genotypes ingested a 20 mg dose of atorvastatin and 10 mg dose of rosuvastatin with a washout period of 1 week. Subjects with the SLCO1B1 c.521CC genotype (n=4) had a 144% (P<0.001) or 61% (P=0.049) greater mean area under the plasma atorvastatin concentration-time curve from 0 to 48 h (AUC(0-48 h)) than those with the c.521TT (n=16) or c.521TC (n=12) genotype, respectively. The AUC(0-48 h) of 2-hydroxyatorvastatin was 100% greater in subjects with the c.521CC genotype than in those with the c.521TT genotype (P=0.018). Rosuvastatin AUC(0-48 h) and peak plasma concentration (Cmax) were 65% (P=0.002) and 79% (P=0.003) higher in subjects with the c.521CC genotype than in those with the c.521TT genotype. These results indicate that, unexpectedly, SLCO1B1 polymorphism has a larger effect on the AUC of atorvastatin than on the more hydrophilic rosuvastatin.
Abstract: BACKGROUND: Both atorvastatin and rifampicin are substrates of OATP1B1 (organic anion transporting polypeptide 1B1) encoded by SLCO1B1 gene. Rifampicin is a potent inhibitor of SLCO1B1 (IC50 1.5 umol/l) and SLCO1B1 521T>C functional genetic polymorphism alters the kinetics of atorvastatin in vivo. We hypothesize that rifampicin might influence atorvastatin kinetics in a SLCO1B1 polymorphism dependent manner. METHODS: Sixteen subjects with known SLCO1B1 genotypes (6 c.521TT, 6 c.521TC and 4 c.521CC) were divided into 2 groups (atorvastatin-placebo group, n=8; atorvastatin-rifampicin group, n=8) randomly. In this 2-phase crossover study, atorvastatin (40 mg single-oral dose) pharmacokinetics after co-administration of placebo and rifampicin (600 mg single-oral dose) were measured for up to 48 h by liquid chromatography-mass spectrometry (LC-MS). In the third phase, rifampicin (450 mg single-oral dose) pharmacokinetics was measured additionally. RESULTS: Rifampicin increased atorvastatin plasma concentration in accordance with SLCO1B1 521T>C genotype while the increasing percentage of AUC((0-48)) among c.521TT, c.521TC and c.521CC individuals were 833+/-245% vs 468+/-233% vs 330+/-223% (P=0.007). However, SLCO1B1 521T>C exerted no impact on rifampicin pharmacokinetics (P>0.05). CONCLUSIONS: These results suggested that rifampicin elevated the plasma concentration of atorvastatin depending on SLCO1B1 genotype and rifampicin pharmacokinetics were not altered by SLCO1B1 genotype.
Abstract: The ABCG2 c.421C>A single-nucleotide polymorphism (SNP) was determined in 660 healthy Finnish volunteers, of whom 32 participated in a pharmacokinetic crossover study involving the administration of 20 mg atorvastatin and rosuvastatin. The frequency of the c.421A variant allele was 9.5% (95% confidence interval 8.1-11.3%). Subjects with the c.421AA genotype (n = 4) had a 72% larger mean area under the plasma atorvastatin concentration-time curve from time 0 to infinity (AUC(0-infinity)) than individuals with the c.421CC genotype had (n = 16; P = 0.049). In participants with the c.421AA genotype, the rosuvastatin AUC(0-infinity) was 100% greater than in those with c.421CA (n = 12) and 144% greater than in those with the c.421CC genotype. Also, those with the c.421AA genotype showed peak plasma rosuvastatin concentrations 108% higher than those in the c.421CA genotype group and 131% higher than those in the c.421CC genotype group (P < or = 0.01). In MDCKII-ABCG2 cells, atorvastatin transport was increased in the apical direction as compared with vector control cells (transport ratio 1.9 +/- 0.1 vs. 1.1 +/- 0.1). These results indicate that the ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and, even more so, of rosuvastatin-potentially affecting the efficacy and toxicity of statin therapy.
Abstract: To identify pharmacokinetic (PK) drug-drug interactions between tipranavir-ritonavir (TPV/r) and rosuvastatin and atorvastatin, we conducted two prospective, open-label, single-arm, two-period studies. The geometric mean (GM) ratio was 1.37 (90% confidence interval [CI], 1.15 to 1.62) for the area under the concentration-time curve (AUC) for rosuvastatin and 2.23 (90% CI, 1.83 to 2.72) for the maximum concentration of drug in serum (Cmax) for rosuvastatin with TPV/r at steady state versus alone. The GM ratio was 9.36 (90% CI, 8.02 to 10.94) for the AUC of atorvastatin and 8.61 (90% CI, 7.25 to 10.21) for the Cmax of atorvastatin with TPV/r at steady state versus alone. Tipranavir PK parameters were not affected by single-dose rosuvastatin or atorvastatin. Mild gastrointestinal intolerance, headache, and mild reversible liver enzyme elevations (grade 1 and 2) were the most commonly reported adverse drug reactions. Based on these interactions, we recommend low initial doses of rosuvastatin (5 mg) and atorvastatin (10 mg), with careful clinical monitoring of rosuvastatin- or atorvastatin-related adverse events when combined with TPV/r.
Abstract: Telaprevir is a hepatitis C virus protease inhibitor that is both a substrate and an inhibitor of CYP3A. Amlodipine and atorvastatin are both substrates of CYP3A and are among the drugs most frequently used by patients with hepatitis C. This study was conducted to examine the effect of telaprevir on atorvastatin and amlodipine pharmacokinetics (PK). This was an open-label, single sequence, nonrandomized study involving 21 healthy male and female volunteers. A coformulation of 5 mg amlodipine and 20 mg atorvastatin was administered on day 1. Telaprevir was taken with food as a 750-mg dose every 8 h from day 11 until day 26, and a single dose of the amlodipine-atorvastatin combination was readministered on day 17. Plasma samples were collected for determination of the PK of telaprevir, amlodipine, atorvastatin, ortho-hydroxy atorvastatin, and para-hydroxy atorvastatin. When administration with telaprevir was compared with administration without telaprevir, the least-square mean ratios (90% confidence limits) for amlodipine were 1.27 (1.21, 1.33) for the maximum drug concentration in serum (C(max)) and 2.79 (2.58, 3.01) for the area under the concentration-time curve from 0 h to infinity (AUC(0-∞)); for atorvastatin, they were 10.6 (8.74, 12.9) for the C(max) and 7.88 (6.84, 9.07) for the AUC(0-∞). Telaprevir significantly increased exposure to amlodipine and atorvastatin, consistent with the inhibitory effect of telaprevir on the CYP3A-mediated metabolism of these agents.
Abstract: BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.