Identification of the rate-determining process in the hepatic clearance of atorvastatin in a clinical cassette microdosing study

Clin Pharmacol Ther. 2011 Oct;90(4):575-81. doi: 10.1038/clpt.2011.142. Epub 2011 Aug 10.


Clearance of atorvastatin occurs through hepatic uptake by organic anion transporting polypeptides (OATPs) and subsequent metabolism by cytochrome P450 (CYP) 3A4. To demonstrate the relative importance of OATPs and CYP3A4 in the hepatic elimination of atorvastatin in vivo, a clinical cassette microdose study was performed. A cocktail consisting of a microdose of atorvastatin along with probe substrates for OATPs (pravastatin) and CYP3A4 (midazolam) was orally administered to eight healthy volunteers. The pharmacokinetics of this cocktail was observed at baseline, after an oral dose of 600 mg rifampicin (an inhibitor of OATPs), and after an intravenous dose of 200 mg itraconazole (a CYP3A4 inhibitor). Rifampicin increased the pravastatin dose-normalized area under the plasma concentration-time curve (AUC) (4.6-fold), and itraconazole significantly increased the midazolam dose-normalized AUC (1.7-fold). The atorvastatin dose-normalized AUC increased 12-fold when coadministered with rifampicin but did not change when coadministered with itraconazole. These results indicate that hepatic uptake via OATPs makes the dominant contribution to the hepatic elimination of atorvastatin at a subtherapeutic microdose.

Publication types

  • Clinical Trial, Phase I
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Atorvastatin
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors
  • Dose-Response Relationship, Drug
  • Heptanoic Acids / administration & dosage*
  • Heptanoic Acids / blood
  • Heptanoic Acids / metabolism*
  • Humans
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Metabolic Clearance Rate / drug effects
  • Metabolic Clearance Rate / physiology
  • Midazolam / administration & dosage
  • Midazolam / blood
  • Midazolam / metabolism
  • Organic Anion Transporters / antagonists & inhibitors
  • Organic Anion Transporters / metabolism
  • Pravastatin / administration & dosage
  • Pravastatin / blood
  • Pravastatin / metabolism
  • Pyrroles / administration & dosage*
  • Pyrroles / blood
  • Pyrroles / metabolism*
  • Time Factors
  • Young Adult


  • Cytochrome P-450 CYP3A Inhibitors
  • Heptanoic Acids
  • Organic Anion Transporters
  • Pyrroles
  • Atorvastatin
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Pravastatin
  • Midazolam