Lovastatin

In medicine and pharmacology, lovastatin is a member of the statin family, used to lower cholesterol and prevent cardiovascular diseases.

Lovastatin, a substance derived from Aspergillus terreus, was together with mevastatin (now called compactin) one of the first statins obtained in the late 1970s. one of the Galien Awards for pharmaceutical research, specifically in 1991. It was discovered by Sagrario Mochales, a Spanish microbiologist.

Description

Lovastatin is a white, crystalline powder, insoluble in water and sparingly soluble in solvents such as ethanol, methanol, and acetonitrile. Like simvastatin, lovastatin is actually a lactone, pharmacologically inactive. It is its β-hydroxy derivative (lovastatin β-hydroxy acid or lovastatin acid) that is actually active in the body.

Pharmacokinetics

Routes of administration (forms of use)

Orally.

Absorption

Absorption, like most statins, is limited, reducing to a maximum of 30%. It undergoes a first-pass metabolic effect. This together with the low absorption gives it a very low bioavailability, around 5%. Various studies show that its absorption on an empty stomach is 2/3 of that registered immediately after meals.

Distribution

Plasma protein binding is greater than 95%, diffusing the blood-brain and placental barriers. The maximum peak in plasma is reached approximately after two hours.

Metabolism and metabolites

Metabolism is hepatic. The main active metabolites present in human plasma are lovastatin β-hydroxy acid, its 6'-hydroxy derivatives, and two other metabolites. Lovastatin is a CYP3A4 substrate, which is of interest when assessing interactions with other drugs.

Excretion

80% is eliminated in feces, and 10% in urine.

Pharmacodynamics

Via de la HMG CoA reductasa.

Mechanism of action

Lovastatin β-hydroxy acid is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). This enzyme catalyzes an essential step in the mevalonate pathway, the conversion of HMG-CoA to mevalonate, which is a key metabolite in cholesterol biosynthesis. The attached diagram shows the blocking level of statins as well as other substances in the biosynthesis of cholesterol. The inhibition of the enzyme is carried out competitively.

The blockade of the hepatic synthesis of cholesterol causes an activation of the regulatory proteins SREBP (sterol regulatory elements-binding proteins), which activate the transcription of proteins and, therefore, they produce increased expression of the LDL receptor gene and an increase in the number of functional receptors in the hepatocyte.

Effects

As a consequence of the inhibition of HMG-CoA reductase, the levels of total cholesterol and LDL decrease, substances closely related to atherosclerosis and increased cardiovascular risk. Apolipoprotein B is also substantially decreased during treatment with simvastatin. In addition, it moderately increases HDL-C and reduces plasma triglycerides. As a result of these changes, the ratio of total cholesterol to HDL cholesterol, as well as the ratio of LDL cholesterol to HDL cholesterol, are reduced.

Since the publication of studies such as the Framingham Heart, the Seven Countries or the MRFIT, the role of hypercholesterolemia as a factor in of main risk in episodes of morbidity and mortality of cardiovascular origin.^, With studies such as the Lipid Research Clinics Coronary Primary Prevention or the Helsinki Heart lowering cholesterol was shown to prevent the onset of these cardiovascular events.^,

Interactions

Pharmacodynamic interactions: Both fibrates and niacin (nicotinic acid) increase the risk of myopathy associated with lovastatin. This is especially important in the case of gemfibrozil, which, in addition to interacting at the receptor level, interferes with hepatic metabolism at the CYP3A4 level.

Pharmacokinetic interactions: A large part of the interactions of lovastatin, like most statins, will be determined by the fact that it is a substrate of CYP3A4. Thus, in relation to hepatic metabolism we can find:

Clinical use

Lovastatin is used for the control of hypercholesterolemia and in the prevention of cardiovascular disease.

Clinical trials.

Along with those already mentioned above, the following are of interest:

• AFCAPS (Air Force Coronary Atherosclerosis Prevention Study), with 6605 patients and performed with lovastatin.
• EXCEL study.
• ADVOCATE Studythe ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation). Indirect study of lovastatin associated with niacin, comparing it with atorvastatin and simvastatin.
• Post-CABG StudyPost- Coronary Artery Bypass Grafting Trial), with 1351 patients and the use of lovastatin.
• ACAPS Study (ACAPS Study)the Asymptomatic Carotid Artery Progression Study), with 919 patients and study of lovastatin.
• CCAIT Study (CCAIT)Canadian Coronary Atherosclerosis Intervention Trial). 331 patients with lovastatin, which led to an interesting substudy in women.
• Estudio MARS (Mars Study)the Monitored Atherosclerosis Regression Study). Angiographic study carried out with 188 patients and assessment of the effects of lovastatin on the regression of the ateroma plate.

Innumerable other clinical trials have been carried out to try to demonstrate the usefulness of statins in other pathologies, such as osteoporosis, Parkinson's disease, Alzheimer's disease, or septic shock.^{, ,,}

Indications

• Hypercholesterolemia.
  • Primary hypercholesterolemia or mixed dyslipidemia.
  • Family hypercholesterolemia homozigota
• Cardiovascular prevention.
  • Reduction of cardiovascular morbidity in patients with manifest atherosclerotic cardiovascular disease.
  • Reduction of cardiovascular morbidity in patients with diabetes mellitus, with normal or high cholesterol levels.
  • Supplementary treatment to the correction of other risk factors and other cardioprotective treatments.

Adverse effects

For the assessment of adverse reactions (ADRs) the CIOSM criteria will be taken into account.

Contraindications

• Hypersensitivity to lovastatin or any of the excipients.
• Active liver disease or unexplained persistent elevations of serum transamines.
• Pregnancy and breastfeeding.
• Concomitant administration of CYP3A4 powerful inhibitors.

Introductions

20 and 40 mg tablets.

Among the usual excipients for this product we can find:

• Lactose.
• Pregelatinized starch.
• Cellulose microcrystalline. (E460 I)
• Magnetic stearate. (E470 B)
• Butilhidroxianisol. (E320)
• Blue FD student body no.2 (Indigotina) (E132)
• Yellow quinoleine alumin. (E104)
• Red iron oxide. (E172)