Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease.
Atorvastatin lowers plasma
low-density lipoprotein (
LDL) cholesterol levels by inhibition of
HMG-CoA reductase. The mean dose-response relationship has been shown to be log-linear for
atorvastatin, but plasma concentrations of
atorvastatin acid and its metabolites do not correlate with
LDL-cholesterol reduction at a given dose. The clinical dosage range for
atorvastatin is 10-80 mg/day, and it is given in the
acid form.
Atorvastatin acid is highly soluble and permeable, and the
drug is completely absorbed after
oral administration. However,
atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The volume of distribution of
atorvastatin acid is 381L, and
plasma protein binding exceeds 98%.
Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine. In vitro,
atorvastatin acid is a substrate for
P-glycoprotein, organic
anion-transporting
polypeptide (OATP) C and H+-monocarboxylic
acid cotransporter. The total plasma clearance of
atorvastatin acid is 625 mL/min and the half-life is about 7 hours. The renal route is of minor importance (<1%) for the elimination of
atorvastatin acid. In vivo,
cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the
acid and the
lactone forms of
atorvastatin.
Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3.
Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of
atorvastatin acid after
oral administration, as indicated by decreased peak concentration and increased time to peak concentration. Women appear to have a slightly lower plasma exposure to
atorvastatin for a given dose.
Atorvastatin is subject to metabolism by
CYP3A4 and cellular membrane transport by OATP C and
P-glycoprotein, and
drug-drug interactions with potent inhibitors of these systems, such as
itraconazole,
nelfinavir,
ritonavir,
cyclosporin,
fibrates,
erythromycin and grapefruit juice, have been demonstrated. An interaction with
gemfibrozil seems to be mediated by inhibition of glucuronidation. A few case studies have reported
rhabdomyolysis when the pharmacokinetics of
atorvastatin have been affected by interacting drugs.
Atorvastatin increases the bioavailability of
digoxin, most probably by inhibition of
P-glycoprotein, but does not affect the pharmacokinetics of
ritonavir,
nelfinavir or
terfenadine.