Atorvastatin ADME

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this pathway in the Pathway Browser
Atorvastatin (ATV, brand name Lipitor), is a lipid-lowering drug of the statin class of medications. It inhibits the endogenous production of cholesterol in the liver, thereby lowering abnormally high cholesterol and lipid levels, and ultimately reducing the risk of cardiovascular disease. Statins inhibit the enzyme hydroxymethylglutaryl-coenzyme A reductase (HMGCR) , which catalyzes the critical step in cholesterol biosynthesis of HMG-CoA conversion to mevalonic acid. Statins are the most commonly prescribed medication for treating abnormal lipid levels (Malhotra & Goa 2001). ATV and its hydroxy-metabolites collectively inhibit HMGCR to reduce circulating low-density lipoprotein cholesterol.

ATV is transported in the blood almost exclusively bound to plasma proteins (>98%) (Lennernas 2003), and is subject to pre‑systemic clearance at the gastrointestinal tract and to first‑pass hepatic clearance, which explains its low systemic bioavailability (~12%) (Garcia et al. 2003). 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 (Kalliokoski & Niemi 2009).

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 (Schachter 2005).
Literature References
PubMed ID Title Journal Year
20678686 Pharmacokinetics and bioequivalence evaluation of two different atorvastatin calcium 10-mg tablets: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy fasted Chinese adult males

Lu, C, Zhang, MQ, Liu, GY, Jia, JY, Pu, HH, Yu, C, Weng, LP, Li, GX, Wang, W, Liu, YM, Xu, RJ

Clin Ther 2010
19785645 Impact of OATP transporters on pharmacokinetics

Niemi, M, Kalliokoski, A

Br J Pharmacol 2009
15660968 Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update

Schachter, M

Fundam Clin Pharmacol 2005
11693468 Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia

Malhotra, HS, Goa, KL

Drugs 2001
14531725 Clinical pharmacokinetics of atorvastatin

Lennernäs, H

Clin Pharmacokinet 2003
12949632 Clinical pharmacokinetics of statins

García, MJ, Prous, JR, Sánchez Navarro, A, Reinoso, RF

Methods Find Exp Clin Pharmacol 2003
Event Information
Orthologous Events
Cite Us!