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PHARMACOKINETICS

The disposition and metabolism of atorvastatin was investigated in mice administered an oral dose of [14C]atorvastatin (free acid). Peak plasma radioactivity concentrations occurred 1 hr postdose after both single- and multiple-dose administration and declined rapidly thereafter. Total plasma radioactivity levels in mice receiving the multiple dose were approximately 50% of levels observed after single-dose administration. Plasma metabolic profiles, which provided evidence of extensive metabolism, remained similar. Feces was the major route of atorvastatin-derived radioactivity elimination. Fecal profiles showed extensive metabolism with qualitatively similar profiles after single- and multiple-dose administration; however, quantitative differences were apparent. Metabolites identified in plasma and feces include hydroxylated, beta-oxidized, and unsaturated derivatives of atorvastatin. Most metabolites had undergone beta-oxidation. In mice receiving multiple 1mg/kg doses of atorvastatin, no effect on spectral P450 concentration was found, and only a minor increase was observed at the 200 mg/kg dose level. Catalytic activities of CYP4501A, -2B, and -3A were not significantly affected; CYP4A activity decreased in a dose-dependent manner. Administration of multiple doses resulted in lower systemic plasma levels of total atorvastatin-derived radioactivity not readily explained by these studies. In mice, the majority of metabolites are formed primarily through the beta-oxidation pathway.⁽¹⁸⁾

Bile was a major route of [(14)C] drug-derived excretion, accounting for 73 and 33% of the oral dose in the rat and dog, respectively. The remaining radioactivity was recovered in the feces; only trace amounts were excreted in urine. Radioactive components identified in rat and dog bile were the para- and ortho-hydroxy metabolites, a glucuronide conjugate of ortho-hydroxy atorvastatin and unchanged atorvastatin. Two minor radioactive components were identified as beta-oxidation products of atorvastatin with one confirmed as a beta-oxidized atorvastatin derivative. Biliary recycling was found to be an important component in atorvastatin metabolism. Multiple dose administration in rats did not alter biliary metabolic profiles. Rat and dog plasma profiles after multiple dose administration were similar and showed no additional metabolites not found in bile. Examination of rat and dog bile and plasma indicates that atorvastatin  primarily undergoes oxidative metabolism.⁽¹⁹⁾

The absorption, distribution and excretion of radioactivity were investigated after repeated oral administration of 14C-atorvastatin at 1 mg/kg once daily for 21 days to male rats. Also, the transfer to fetuses, milk and suckling pups were investigated after single oral administration of 14C-atorvastatin at 1 mg/kg to pregnant or lactating rats. 1) During the course of repeated administration, plasma levels of radioactivity at 24 hr after daily dosing reached a steady state after the 2nd dosing. The steady state plasma levels of radioactivity varied with a range of 2.1 to 4.1 times higher than that after the 1st dosing. After the 21st dosing, plasma levels of radioactivity reached its maximum of 17.5 ng eq./mL at 2.7 hr and then declined with a terminal half-life of 12.0 hr. 2) During the course of repeated administration, concentrations of radioactivity in most tissues increased with the number of dose. In any cases, however, the increases at 4 and 24 hr after the 21st dosing were less than 2.7 and 4.1 times, respectively. After the 21st dosing, in most tissues, levels of radioactivity attained the maxima at 4 hr, and thereafter decreased with time. At all the sampling points, the highest concentrations of radioactivity were observed in the liver. Whole-body autoradiograms showed similar distribution of radioactivity, and at 168 hr after the 21st dosing low radioactivity was found only in the liver, intestinal contents and gastric wall. 3) During the course of repeated administration, excretion profiles of radioactivity in urine and feces up to 24 hr after daily dosing remained fairly constant from Day 5. Up to 168 hr after the last dosing, 0.3 and 96.4% of the cumulative dose were excreted in urine and feces, respectively. 4) Whole-body autoradiograms of rats on Days 13 and 18 of pregnancy showed trace levels of radioactivity in the fetuses. After administration to rats on Day 18 of pregnancy, radioactivity was found in the fetal tissues. Although fetal liver and digestive tract showed relatively high concentrations, percentage of radioactivity transferred per fetus was 0.00% of the administered dose. 5) After administration to lactating rats, radioactivity in milk reached the maximum of 17.1 ng eq./mL at 6.0 hr and thereafter declined with a half-life of 7.8 hr. When compared with the plasma levels determined simultaneously, Cmax in milk appeared later and then declined more slowly. In suckling pups, radioactivity was detected only in the liver, clotted milk in the stomach and carcass, and the levels in the other tissues were below the detection limit.⁽²⁰⁾