Fenostat Mechanism of Action

Lipid Modifying Agent (HMG-CoA Reductase Inhibitor/Fibrate).
Pharmacology: Pharmacodynamics: Atorvastatin: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolised primarily through the receptor with high affinity to LDL (LDL receptor).
Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolemia, a population that has not usually responded to lipid-lowering medicinal products.
Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality.
Fenofibrate: Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type alpha (PPARα).
Through activation of PPARα, fenofibrate increases the lipolysis and elimination of atherogenic triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein CIII. Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII.
The previously stated effects of fenofibrate on lipoproteins lead to a reduction in very low- and low density fractions (VLDL and LDL) containing apoprotein B and an increase in the high density lipoprotein fraction (HDL) containing apoprotein AI and AII.
In addition, through modulation of the synthesis and the catabolism of VLDL fractions fenofibrate increases the LDL clearance and reduces small dense LDL, the levels of which are elevated in the atherogenic lipoprotein phenotype, a common disorder in patients at risk for coronary heart disease.
Pharmacokinetics: Atorvastatin: Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax) occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. After oral administration, atorvastatin film-coated tablets are 95% to 99% bioavailable compared to the oral solution. The absolute bioavailability of atorvastatin is approximately 12% 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.
Distribution: Mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is ≥98% bound to plasma proteins.
Biotransformation: Atorvastatin is metabolised by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Apart from other pathways these products are further metabolised via glucuronidation. 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.
Elimination: Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, atorvastatin does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours. The half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites.
Fenofibrate: Absorption: Maximum plasma concentrations (Cmax) occur within 4 to 5 hours after oral administration. Plasma concentrations are stable during continuous treatment in any given individual.
The absorption of fenofibrate is increased when administered with food.
Distribution: Fenofibric acid is strongly bound to plasma albumin (more than 99%).
Metabolism and excretion: After oral administration, fenofibrate is rapidly hydrolysed by esterases to the active metabolite fenofibric acid. No unchanged fenofibrate can be detected in the plasma. Fenofibrate is not a substrate for CYP 3A4. No hepatic microsomal metabolism is involved.
The drug is excreted mainly in the urine. Practically all the drug is eliminated within 6 days. Fenofibrate is mainly excreted in the form of fenofibric acid and its glucuronide conjugate. In elderly patients, the fenofibric acid apparent total plasma clearance is not modified.
Kinetic studies following the administration of a single dose and continuous treatment have demonstrated that the drug does not accumulate. Fenofibric acid is not eliminated by hemodialysis.
The plasma elimination half-life of fenofibric acid is approximately 20 hours.
Toxicology: Preclinical Safety Data: Atorvastatin: Atorvastatin was negative for mutagenic and clastogenic potential in a battery of 4 in vitro tests and 1 in vivo assay. Atorvastatin was not found to be carcinogenic in rats, but high doses in mice (resulting in 6-11 fold the AUC_0-24h reached in humans at the highest recommended dose) showed hepatocellular adenomas in males and hepatocellular carcinomas in females. There is evidence from animal experimental studies that HMG-CoA reductase inhibitors may affect the development of embryos or fetuses. In rats, rabbits and dogs atorvastatin had no effect on fertility and was not teratogenic, however, at maternally toxic doses fetal toxicity was observed in rats and rabbits. The development of the rat offspring was delayed and post-natal survival reduced during exposure of the dams to high doses of atorvastatin. In rats, there is evidence of placental transfer. In rats, plasma concentrations of atorvastatin are similar to those in milk. It is not known whether atorvastatin or its metabolites are excreted in human milk.
Fenofibrate: In a three-month oral nonclinical study in the rat species with fenofibric acid, the active metabolite of fenofibrate, toxicity for the skeletal muscles (particularly those rich in type I-slow oxidative-myofibres) and cardiac degeneration, anemia and decreased body weight were seen. No skeletal toxicity was noted at doses up to 30 mg/kg (approximately 17-time the exposure at the human maximum recommended dose (MRHD). No sign of cardiomyotoxicity were noted at an exposure about 3 times the exposure at MRHD. Reversible ulcers and erosions in the gastro-intestinal tract occurred in dogs treated for 3 months. No gastro-intestinal lesions were noted in that study at an exposure approximately 5 times the exposure at the MRHD. Studies on mutagenicity of fenofibrate have been negative. In rats and mice, liver tumors have been found at high dosages, which are attributable to peroxisome proliferation. These changes are specific to small rodents and have not been observed in other animal species. This is of no relevance to therapeutic use in man. Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryotoxic effects were observed at doses in the range of maternal toxicity. Prolongation of the gestation period and difficulties during delivery were observed at high doses. Reversible hypospermia and testicular vacuolation and immaturity of the ovaries were observed in a repeat-dose toxicity study with fenofibric acid in young dogs. However, no effects on fertility were detected in non-clinical reproductive toxicity studies conducted with fenofibrate.