From Proteopedia

Atorvastatin

Atorvastatin, commercially known as Lipitor is a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA Reductase) inhibitor that works primarily in the liver^[1]. It is part of a class of medications known as statins that are cholesterol-lowering medications^[2]. HMG-CoA reductase catalyzes the committed step in cholesterol synthesis, so by inhibiting this step, low density lipoprotein (LDL) cholesterol can be effectively lowered as well as increasing high density lipoprotein (HDL) levels. By lowering LDL, the likelihood of stroke and heart attack can be decreased^[3].

Bruce Roth, a Phizer employee, first synthesized atorvastatin in 1985. In 2008 Lipitor was the top-selling pharmaceutical in the world with $12.4 billion in sales. However, Lipitor's US patent protection is scheduled to expire in June 2011^[4].

Chemical Properties

Formula: C₃₃H₃₅FN₂O₅

Molecular Mass: 558.64 g/mol

Half life: 14 hours

Half-life of HMG-CoA inhibitor activity: 20-30 hours

Structure and Synthesis

Comparison of HMG-CoA and Atorvastatin

When synthesizing a statin, four properties need to be taken into consideration: high affinity for the HMG-CoA reductase active site, selective uptake into hepatic cells instead of non-hepatic cells, low endogenous inhibitory equivalents, and a relatively long half-life/duration of effect.

The essential structural unit of all statins, including atorvastatin, is the dihydroxyheptanoic acid unit and a multi-substituted ring system. It is also important for the statin to be structurally similar to the endogenous substrate, HMG-CoA, and the mevaldyl-CoA transition state intermediate. Statins also need to have specific stereochemistry because HMG-CoA reductase is stereoselective^[5].

Considerations When Taking Atorvastatin

Atorvastatin should be taken only in conjuction with a complete cholesterol-lowering program which includes diet, exercise, and weight control^[6].

Side Effects

There are numerous side effects that can occur from taking atorvastatin. The most serious side effect although the most rare is myopathy (muscular weakness) with increased levels of creatinine kinase and rhabdomyolysis (rapid breakdown of skeletal muscle). Other more common side effects include headache, weakness, insomnia, peripheral edema, urinary tract infections, and flu-like symptoms^[7]. Atorvastatin has also been shown to elevate the levels of alanine transaminase (ALT) and aspartate transaminase (AST)^[8].

Atorvastatin has been shown to cause fetal harm in pregnant women, so should never be prescribed in women who are pregnant. Cholesterol levels and triacylglycerols increase naturally during pregnancy and are essential for the development of the fetus, and slowing production of cholesterol could have detrimental effects on the fetus ^[9].

Adverse Food and Drug Interactions

Atorvastatin can interact with many other drugs including, digoxin (E.g. digitalis),warfarin, erythromycin, fenofibrate (E.g. Tricor), niacin, certain antifungal medications (E.g. Diflucan), certain cancer medications and steroids, and HIV/AIDS medications^[10].

Vitamin D actually lowers atorvastatin active metabolite concentrations^[11]. Interestingly, grapefruit juice in co-administration with atorvastatin increases atorvastatin's Cmax (rate of absorption) and AUC (extent of absorption) which can lead to adverse effects. Grapefruit juice is a known inhibitor of Cytochrome P450 3A4 (CYP3A4), which is involved in the deactivation of avtorvastatin for excretion from the body^[12].

Targets

Atorvastatin's main target is HMG-CoA Reductase, however, it also can target Dipeptidyl peptidase 4 and Aryl hydrocarbon receptor^[13].

HMG-CoA Reductase

HMG-CoA is an endoplasmic reticulum transmembrane glycoprotein. It is a tetramer and an NADPH-dependent enzyme. HMG-CoA reductase contains an N-terminal membrane domain and a C-terminal catalytic domain. The catalytic portion can be further subdivided into an N-domain (N-terminal), a large L-domain, and a small S-domain. The L-domain binds the substrate, and the S-domain binds NADP^[14].

Mechanism of Action

Cholesterol Synthesis Pathway

In the normal catalytic mechanism of converting HMG-CoA to mevalonate, the carboxyl group of hydroxymethylglutarate that is in ester linkage to the thiol of coenzyme A is reduced twice via NADPH to an aldehyde and then to an alcohol.

HMG-CoA Reductase Mechanism

HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate in the cholesterol biosynthesis pathway. Atorvastatin selectively and competitively inhibits HMG-CoA reductase. The inhibition subsequently increases the expression of LDL receptors on hepatocytes, which increases LDL uptake by hepatocytes, therefore decreasing the LDL-cholesterol concentration in the blood. Atorvastatin also increases levels of HDL-cholesterol.^[15]

Active Site

The active sites of HMG-CoA reductase are located at the interface of the two monomers of a dimer. Each active site has a loop that folds over part of the binding pocket; the loop contains an unusual cis-peptide bond that is highly conserved. The loop folds over the active site when both substrates (HMG-CoA and NADPH) are bound to exclude solvent from the active site.

Dipeptidyl peptidase 4 and Aryl hydrocarbon receptor

Atorvastatin is also an inhibitor of dipeptidyl peptidase 4, although it has no pharmacological effects. Dipeptidyl peptidase 4 removes N-terminal didpeptides from polypeptides and plays a role in T-cell activation, amino acid transport and metabolism^[16].

Atorvastatin also is an agonist of aryl hydrocarbon receptor. Aryl hydrocarbon receptor is a ligand-activated transcriptional activator that binds to the promoter region of genes it activates. It specifically activates the expression of multiple phase I and II xenobiotic metabolizing enzyme genes (E.g. CYP3A4. Aryl hydrocarbon receptor also mediates the biochemical and toxic effects of halogenated aromatic hydrocarbons, cell-cycle regulation, and plays an important role in the development and maturation of tissues.^[17]

References