Tonact-FN Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Atorvastatin: Atorvastatin is a selective competitive inhibitor of 3-hydroxy-3-methyl-glutarylcoenzyrne A (HMG-CoA) reductase enzyme. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the synthesis of cholesterol.
The primary site of action of HMG-CoA reductase inhibitors is the liver. Inhibition of cholesterol synthesis in the liver leads to upregulation of low density lipoprotein (LDL) receptors and an increase in LDL-catabolism. There is also some reduction of LDL-production as a result of inhibition of hepatic synthesis of very low density lipoprotein (VLDL), the precursor of LDL-cholesterol. Atorvastatin reduces total cholesterol, LDL-cholesterol and apolipoprotein (apo) B in patients with homozygous and heterozygous familial hypercholesterolemia, non familial forms of hypercholesterolemia and mixed dyslipidemias. Atorvastatin also reduces VLDL-cholesterol and triglycerides and produces variable increases in high density lipoprotein (HDL)-cholesterol and apo AI. Atorvastatin reduces total cholesterol, LDL-cholesterol, VLDL-cholesterol, apo B, triglycerides, and non-HDL-cholesterol, and increases HDL-cholesterol in patients with isolated hypertriglyceridemia. Atorvastatin also reduces intermediate density lipoprotein (IDL) cholesterol in patients with dysbetalipoproteinemia.
Atorvastatin as well as some of its metabolites are pharmacologically active in humans. Drug dosage rather than systemic drug concentration correlates better with LDL-cholesterol reduction. Individualization of drug dosage should be based on therapeutic response.
Fenofibrate: Fenofibrate is a lipid regulating agent. Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total-C, LDL-C, apo B, total triglycerides and VLDL in treated patients. In addition, treatment with fenofibrate results in increases in HDL-C and apoproteins apo AI and apo AII. The effects of fenofibric acid seen in clinical practice have been explained by the activation of peroxisome proliferator activated receptor (alpha) [PPAR (alpha)]. Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation) to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPAR (alpha) also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.
Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.
Pharmacokinetics: Atorvastatin: Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by peak concentration (C_max) and area under the curve (AUC), LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for C_max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration.
Distribution: Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is >98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk.
Metabolism: Atorvastatin is extensively metabolized to ortho-and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 1-4 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Special Populations: Geriatric: Plasma concentrations of atorvastatin are higher (approximately 40% for C_max and 30% for AUC) in healthy elderly subjects (age >65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults.
Pediatric: Pharmacokinetic data in the pediatric population are not available.
Gender: Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for C_max and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.
Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary.
Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.
Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C_max and AUC are each 4-fold greater to patients with Childs-Pugh A disease. C_max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease.
Fenofibrate: Absorption: After fenofibrate is dissolved, fenofibrate is well absorbed from the gastrointestinal tract. Its bioavailability is optimized when taken with meals.
Distribution: In healthy volunteers administered formulation of fenofibrate, steady-state plasma levels of fenofibric acid were shown to be achieved within 5 days of daily dosing with single oral doses and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% bound to plasma proteins in normal and hyperlipidemic subjects.
Metabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma of healthy subjects following fenofibrate administration. Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.
In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.
Excretion: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabeled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. Fenofibric acid is eliminated with a half-life of approximately 16 hours, allowing once daily administration in a clinical setting.
Special Populations: Geriatrics: A study using formulation of fenofibrate shows that the oral clearance of fenofibric acid is similar to that of young adults. This indicates that a similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites.
Pediatrics: Fenofibrate has not been investigated in adequate and well-controlled trials in pediatric patients.
Gender: No pharmacokinetic difference between males and females has been observed for fenofibrate.
Renal Impairment: In a study using formulation in patients with severe renal impairment (creatinine clearance <50 mL/min), the rate of clearance of fenofibric acid was greatly reduced, and the compound accumulated during chronic dosage. However, in patients having moderate renal impairment (creatinine clearance of 50 to 90 mL/min), the oral clearance and the oral volume of distribution of fenofibric acid are increased compared to healthy adults. Therefore, the dosage of fenofibrate should be minimized in patients who have severe renal impairment, while no modification of dosage is required in patients having moderate renal impairment.
Hepatic Impairment: No pharmacokinetic studies have been conducted in patients with hepatic insufficiency.