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PHARMACOKINETIC PROPERTIES

An enzyme inhibition assay was developed to quantify atorvastatin in human plasma for pharmacokinetic studies. 'The assay is based on the ability of atorvastatin and its metabolites to inhibit the conversion of ¹⁴C-HMG-CoA to ¹⁴C-mevalonate by HMG-CoA rcductase. Atorvastatin is isolated from plasma by protein precipitation and rat liver microsome is used to provide the reductase. The precision and accuracy of the assay is within ± 15% and ± 8% respectively. Atorvastatin and its metabolites are stable at -20°C and the assay is reproducible over a 6-month period.⁽²¹⁾ The limit of quantification is 0.36mg/l. Atorvastatin plasma concentrations may also be analyzed by a gas chromatography/mass spectrometry assay for unmetabolised atorvastatin.⁽²²⁾

Atorvastatin is highly soluble and permeable, and the drug is completely absorbed after oral administration. Peak Plasma concentrations occur within 1 to 2 hours. The extent of absorption increases in proportion to atorvastatin dose. However, atorvastatin is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The systemic availability HMG-CoA reductase activity is approximately 30%.⁽¹⁾

Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of atorvastatin  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.⁽²³⁾

Mean maximum plasma atorvastatin equivalent concentration (C_max) and area under the concentration-time curve (AUC) values with food were 47.9% and 12.7% lower, respectively, than without food. Mean time of maximum observed concentration (t_max) and elimination half-life (t_1/2) values were 5.9 and 32.0 hours, respectively, with food and 2.6 and 35.7 hours, respectively, without food. A medium-fat breakfast decreased the rate of atorvastatin absorption significantly, but had little impact on extent of drug absorption.⁽²⁴⁾

Atorvastatin peak concentration and area under the plasma concentration-time curve (AUC) values increased more than proportionally with atorvastatin dose after both single and multiple drug doses. The extent of atorvastatin absorption (AUC) was similar after once- or twice-daily drug administration. Steady-state drug concentrations were achieved by the third day of drug dosing. Mean elimination half-life values ranged from 11 to 24 hours. Atorvastatin accumulation was approximately 1.5- and 3.0-fold after once- and twice-daily administration, respectively. Atorvastatin peak concentration and AUC values increased more than proportionally with atorvastatin dose after both single and multi-drug administration (Table).⁽²⁵⁾

         Table Pharmacokinetic data for atorvastatin

 The volume of distribution of atorvastatin  is 381L, and plasma protein binding exceeds 98%. Atorvastatin  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.⁽²³⁾

A blood:plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Single and multiple-dose whole body autoradiographic studies in rats showed that ¹⁴C-atorvastatin was extensively distributed with highest activity in liver. No ¹⁴C-atorvastatin was measurable in brain, muscles or testes. In the rat, ¹⁴C-atorvastatin is secreted in milk and transferred to foetal tissue. ¹⁴C-atorvastatin did not readily cross the blood brain barrier in rat or dog. Based on observations in rats, atorvastatin is likely to be secreted in human milk.⁽¹⁾

The total plasma clearance of atorvastatin 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 and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyl transferases 1A1 and 1A3. Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by organic anion-transporting polypeptide 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.⁽²³⁾

The C_max of atorvastatin was 42.5% higher in elderly patients (aged 66 to 92 years) than in younger patients (aged 19 to 35 years) and 17.6% higher in women than in men. The mean AUC and half life were 27.3% greater and 36.2% longer, respectively, in elderly adults than in young adults and 11.3% lower and 19.9% shorter in women than in men. The differences were not clinically important.⁽²⁶⁾