Atorvastatin ADME

ATV is transported in the blood almost exclusively bound to plasma proteins (>98%), and is subject to pre‑systemic clearance at the gastrointestinal tract and to first‑pass hepatic clearance, which explains its low systemic bioavailability (~12%). Organic anion transporters OATP1B1, OATP1B3 and OATP2B1, encoded by SLCO1B1, SLCO1B3, and SLCO2B1, respectively are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of drugs such as ATV.

In hepatocytes (and to a lesser extent, the GI tract), ATV can be hydroxylated by cytochrome P450 3A4 (CYP3A4) to hydroxy-metabolites, or undergo lactonization via an unstable acyl glucuronide intermediate to ATV lactone (ATVL) mediated by UGT1A3 and 1A1. ATVL may also be hydroxylated by CYP3A4 to hydroxylactone-metabolites. The lactone metabolites are inactive against HMGCR, but can be hydrolyzed via paraoxonases (PONs) to their corresponding hydroxy acids, which are active against HMGCR. Elimination of ATV and its metabolites is principally biliary with apparently no significant enterohepatic recirculation. Half-life (t1/2) is approximately 14 h for atorvastatin and 20–30 h for its metabolites.