2-hydroxyatorvastatin and 4-hydroxyatorvastatin

Coadministration of statins and fibrates is beneficial in some patients by allowing simultaneous reduction of triglycerides and low-density lipoprotein cholesterol alongside elevation of high-density lipoprotein cholesterol. However, the potential for drug interactions must be taken into consideration. Gemfibrozil increases systemic exposure to various different statins, whereas similar effects are not observed with fenofibrate, suggesting it may be a more appropriate choice for coadministration with statins. Gemfibrozil is reported to cause a moderate increase in the area under the curve (AUC) of atorvastatin, but the effect of fenofibrate on atorvastatin pharmacokinetics has not been described. This study compared the effects of multiple-dose administration of gemfibrozil and fenofibrate on the single-dose pharmacokinetics of atorvastatin. Gemfibrozil coadministration led to significant increases in the AUC of atorvastatin, 2-hydroxyatorvastatin, 2-hydroxyatorvastatin lactone, and 4-hydroxyatorvastatin lactone. In contrast, fenofibrate administration did not lead to clinically meaningful changes in the AUC for atorvastatin, atorvastatin lactone, 2-hydroxyatorvastatin, or 2-hydroxyatorvastatin lactone. The absence of a significant pharmacokinetic interaction between fenofibrate and atorvastatin is consistent with recent results showing no difference in safety profile between atorvastatin as monotherapy or in combination with fenofibric acid. Together, these data suggest that atorvastatin-fenofibrate combination therapy is unlikely to pose a risk to patients.

Topics: Adult; Atorvastatin; Biotransformation; Cross-Over Studies; Drug Interactions; Enzyme Inhibitors; Female; Fenofibrate; Gemfibrozil; Half-Life; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lactones; Male; Middle Aged; Pyrroles

The effect of steady-state istradefylline, an agent for Parkinson's disease with P-glycoprotein and CYP3A inhibitory activity, on the pharmacokinetics of atorvastatin and its metabolites was evaluated in healthy volunteers. A single 40-mg dose of atorvastatin was administered to 20 subjects. After a 4-day washout, subjects received a single 40-mg atorvastatin dose following 40 mg istradefylline (n=16) or placebo (n=4) daily for 14 days. Plasma samples collected for 96 hours after atorvastatin administration, alone and in combination, were analyzed for atorvastatin, orthohydroxy atorvastatin, and parahydroxy atorvastatin. Istradefylline increased atorvastatin C(max) (53%), AUC(0-infinity) (54%), and t((1/2)) (27%); and increased AUC(0-infinity) for orthohydroxy atorvastatin (18%), but had no significant effect on its C(max) or t((1/2)); and had minimal effect on parahydroxy atorvastatin AUC(0-infinity). The lack of inhibition by istradefylline on metabolite systemic exposure, combined with increased atorvastatin systemic exposure, suggests a predominant P-glycoprotein inhibitory effect of istradefylline.

Topics: Administration, Oral; Antiparkinson Agents; Atorvastatin; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biotransformation; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Double-Blind Method; Drug Interactions; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Purines; Pyrroles

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.

Topics: Administration, Oral; Adolescent; Adult; Area Under Curve; Atorvastatin; Bile; Binding, Competitive; Biological Transport; Cell Line; Cross-Over Studies; Enzyme Inhibitors; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Infusions, Intravenous; Liver; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Organic Anion Transporters; Pyrroles; Rifampin; Substrate Specificity; Tablets; Transfection

Itraconazole, a potent inhibitor of CYP3A4, increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by increasing their serum concentrations. The aim of this study was to characterize the effect of itraconazole on the pharmacokinetics of atorvastatin, a new HMG-CoA reductase inhibitor that is metabolized at least in part by CYP3A4.. In a randomized, double-blind, two-phase crossover study, 10 healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days. On day 4, 40 mg atorvastatin was administered orally, and a further dose of 200 mg itraconazole or placebo was taken 24 hours after atorvastatin intake. Serum concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxyatorvastatin acid and lactone, 4-hydroxyatorvastatin acid and lactone, active and total HMG-CoA reductase inhibitors, itraconazole, and hydroxyitraconazole were measured up to 72 hours.. Itraconazole increased the area under the concentration--time curve from time zero to 72 hours [AUC(0-72)] and the elimination half-life of atorvastatin acid about threefold (p < 0.001), whereas the peak serum concentration was not significantly changed. The AUC(0-72) of atorvastatin lactone was increased about fourfold (p < 0.001), and the peak serum concentration and half-life were increased more than twofold (p < 0.01). Itraconazole decreased the peak serum concentration and AUC(0-72) of 2-hydroxyatorvastatin acid (p < 0.01) and 2-hydroxyatorvastatin lactone (p < 0.01). Itraconazole significantly (p < 0.01) increased the half-life of 2 hydroxyatorvastatin lactone. The AUC(0-72) values of active and total HMG-CoA reductase inhibitors were increased 1.6-fold (p < 0.001) and 1.7-fold (p < 0.001), respectively.. Itraconazole has a significant interaction with atorvastatin. The mechanism of increased serum concentrations of atorvastatin and HMG-CoA reductase inhibitors is inhibition of CYP3A4-mediated metabolism of atorvastatin and its metabolites by itraconazole. Concomitant use of itraconazole and other potent inhibitors of CYP3A4 with atorvastatin should be avoided or the dose of atorvastatin should be reduced accordingly.

Topics: Adult; Anticholesteremic Agents; Antifungal Agents; Area Under Curve; Atorvastatin; Cross-Over Studies; Double-Blind Method; Drug Interactions; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl CoA Reductases; Itraconazole; Male; Pyrroles; Smoking

Statins, HMG-CoA reductase inhibitors, are considered the first line treatment of hyperlipidemia to reduce the risk of atherosclerotic cardiovascular diseases. The prevalence of hyperlipidemia and the risk of atherosclerotic cardiovascular diseases are higher in obese patients. Published methods for the quantification of statins and their active metabolites did not test for matrix effect of or validate the method in hyperlipidemic plasma. A sensitive, specific, accurate, and reliable LC-MS/MS method for the simultaneous quantification of simvastatin (SMV), active metabolite of simvastatin acid (SMV-A), atorvastatin (ATV), active metabolites of 2-hydroxy atorvastatin (2-OH-ATV), 4-hydroxy atorvastatin (4-OH-ATV), and rosuvastatin (RSV) was developed and validated in plasma with low (52-103 mg/dl, <300 mg/dl) and high (352-403 mg/dl, >300 mg/dl) levels of triglyceride. The column used in this method was ACQUITY UPLC BEH C18 column (2.1 × 100 mm I.D., 1.7 μm). A gradient elution of mobile phase A (10 mM ammonium formate and 0.04% formic acid in water) and mobile phase B (acetonitrile) was used with a flow rate of 0.4 ml/min and run time of 5 min. The transitions of m/z 436.3 → 285.2 for SMV, m/z 437.2 → 303.2 for SMV-A, m/z 559.2 → 440.3 for ATV, m/z 575.4 → 440.3 for 2-OH-ATV and 4-OH-ATV, m/z 482.3 → 258.1 for RSV, and m/z 412.3 → 224.2 for fluvastatin (internal standard, IS) were determined by Selected Reaction Monitoring (SRM) method to detect transitions ions in the positive ion mode. The assay has a linear range of 0.25 (LLOQ) -100 ng/ml for all six analytes. Accuracy (87-114%), precision (3-13%), matrix effect (92-110%), and extraction recovery (88-100%) of the assay were within the 15% acceptable limit of FDA Guidelines in variations for plasma with both low and high triglyceride levels. The method was used successfully for the quantification of SMV, ATV, RSV, and their active metabolites in human plasma samples collected for an ongoing clinical pharmacokinetic and pharmacodynamic study on patients prior to and post gastric bypass surgery (GBS).

Topics: Adult; Atherosclerosis; Atorvastatin; Calibration; Chromatography, High Pressure Liquid; Female; Gastric Bypass; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; Obesity; Postoperative Period; Preoperative Period; Reproducibility of Results; Rosuvastatin Calcium; Simvastatin; Tandem Mass Spectrometry

A selective, sensitive, and fast high performance liquid chromatography (HPLC) method with mass spectrometric (MS) detection mode has been developed and validated completely in human plasma. Atorvastatin (ATO), p-hydroxy atorvastatin (p-HATO), o-hydroxy atorvastatin (o-HATO) and internal standard (IS) are extracted from human plasma via solid phase extraction (SPE) technique. After elution, the solution is evaporated, then reconstituted with 250 µL of Mobile Phase and analyzed using HPLC/MS/MS system. An isocratic mode is used to separate interference peaks using a Symmetry C-18, 75 × 4.6 mm ID, 3.5 µ, column. The m/z of ATO, o-HATO and p-HATO are 559.2/440.2, 575.3/440.4 and 575.0/440.4 respectively. Linearity ranges are 0.05 to 252.92 ng/mL for ATO, p-HATO and o-HATO respectively. Calibration functions, lower limit of quantitation (LLOQ), stability, intra- and inter-day reproducibility, accuracy, and recovery are estimated. This method is free from matrix effects and any abnormal ionization. This method was successfully applied to a single dose 80 mg tablet bioequivalence (BE) study of Atorvastatin. Copyright © 2011 John Wiley & Sons, Ltd.

Topics: Atorvastatin; Calibration; Chromatography, High Pressure Liquid; Drug Stability; Heptanoic Acids; Humans; Molecular Structure; Pyrroles; Reproducibility of Results; Solid Phase Extraction; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Therapeutic Equivalency

The distribution of single intake atorvastatin in the content of very low, low and high density lipoproteins extracted from blood plasma of healthy volunteers by means of ultracentrifugal separation was investigated. The impact of atorvastatin on the composition of lipoprotein complexes was assessed. It is demonstrated that atorvastatin and its active derivatives transport mainly in the composition of high density lipoproteins. The distribution of atorvastatin and its biologically active metabolites has gender differences. It is established that in males atorvastatin increases the content of triacylglycerides of low density lipoproteins and cholesterol of high density lipoproteins in females.

Topics: Anticholesteremic Agents; Atorvastatin; Biological Transport, Active; Female; Heptanoic Acids; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Male; Pyrroles; Sex Characteristics; Time Factors