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Atorvastatin ADME

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-9754706

PubChem

R-HSA-9754706

Description

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).

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying **all 7** entries
UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
P08183	ATP-dependent translocase ABCB1	ABCB1 MDR1 PGY1	view
P27169	Serum paraoxonase/arylesterase 1	PON PON1	view
P35503	UDP-glucuronosyltransferase 1A3	GNT1 UGT1 UGT1A3	view
Q15166	Serum paraoxonase/lactonase 3	PON3	view
Q92887	ATP-binding cassette sub-family C member 2	ABCC2 CMOAT CMOAT1 CMRP MRP2	view
Q9NPD5	Solute carrier organic anion transporter family member 1B3	LST2 OATP1B3 OATP8 SLC21A8 SLCO1B3	view
Q9Y6L6	Solute carrier organic anion transporter family member 1B1	LST1 OATP1B1 OATP2 OATPC SLC21A6 SLCO1B1	view

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