Lovastatin excretion

Lactation Lovastatin and atorvastatin are excreted in the milk of rats atorvastatin is likely to be excreted in breast milk it is not known whether lovastatin, rosuvastatin, and simvastatin are excreted in breast milk a small amount of pravastatin is excreted in breast milk fluvastatin is present in breast milk in a 2 1 ratio (milk plasma). 

It is clear from Equation (19.4) that saturated fat, not cholesterol, is the single most important factor that raises serum cholesterol. Some cases of hyperlipoproteinemia type IV (high VLDL) respond to low-carbohydrate diets, because the excess of VLDL comes from intestinal cells, where it is produced from dietary carbohydrate. Resins, such as cholestyramine and cholestipol, bind and cause the excretion of bile salts, forcing the organism to use more cholesterol. Lovastatin decreases endogenous cholesterol biosynthesis (see later), and niacin (nicotinic acid) apparently decreases the production of VLDL and, consequently, LDL. It also results in an HDL increase. Antioxidants that inhibit the conversion of LDL to oxidized LDL have also been used with some success. These are high doses of vitamin E and the drug probucol. 

Pravastatin and fluvastatin are almost completely absorbed after oral administration oral doses of lovastatin and simvastatin are absorbed from 30 to 50%. Similarly, pravastatin and fluvastatin are active as such, whereas lovastatin and simvastatin must be hydrolyzed to the acid. Due to first-pass extraction, the primary action of these drugs is on the liver. All are biotransformed, with some of the products retaining activity. Excretion takes place principally through the bile and feces, but some urinary elimination also occurs. Their half-lives range from 1.5 to 2 hours. 

Lovastatin is absorbed to the extent of 30% and undergoes an extensive first-pass hepatic extraction. Lovastatin is converted to the active B hydroxy acid form in the liver. Other metabolites include the 6, hydroxy derivative and two unidentified compounds. About 80% of lovastatin is excreted primarily in feces, about 10% in urine. Concomitant administration with cholestyramine or colestipol may enhance lipid-reducing effects but may decrease bioavailability... 

The hypolipidemic agent pravastatin differs from other HMG-CoA reductase inhibitors (e.g., lovastatin and simvastatin) because it has greater hydrophihcity as a result of the hydroxyl group attached to its decalin ring. The hydro-phihc nature of pravastatin accounts for its minimal penetration into the intracellular space of nonhepatic tissues, including an apparent inability to cross the blood-brain barrier. The drug is also well tolerated because it is rapidly absorbed and excreted, and does not accumulate in plasma even with repeated administration. 

Lovastatin is an inactive prodrug which undergoes in vivo lactone hydrolysis to give the hydroxyacid derivative which is an inhibitor of HMG-CoA reductase. The pharmacokinetic and metabolic profile of lovastatin has been described in detail (3,5,35-37). In the sections below, the absorption, distribution, metabolism, and excretion of lovastatin are briefly reviewed. For this discussion it is helpful to distinguish between active inhibitors (defined as the sum concentration of the hydroxyacid derivative of lovastatin plus other active hydroxyacid metabolites) and total inhibitors (the total concentration of active inhibitors plus lactones and conjugates). Active and totai inhibitors can be separately quantitated by assaying samples before and after ex vivo hydrolysis of plasma samples. 

The excretion of lovastatin has been assessed following an oral dose of C-labeled compound in man. Total recovery of drug equivalents in urine and feces avers ed 10% and 83%. respectively. A substantial amount of radioactivity is also recovered in the feces following intravenous dosing of Relabeled hydroxyacid, indicating that biliary excretion is an important elimination for orally administered lovastatin. 

The most common cause of heart disease is the plaque buildup on artery walls known as atherosclerosis, which was discussed in Section 16.4 in coryunction with the role of diet in plaque formation. If changes in lifestyle do not successfully combat this condition, the next step is cholesterol-lowering drugs, which include lovastatin and cholestyramine. Lovastatin acts by interfering with cholesterol synthesis in the liver. Cholestyramine acts by binding to bile acids in the intestines and accelerating their excretion. This causes the hver to convert more cholesterol into bUe acids, leaving less to enter the circulatory system. 

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