Atorvastatin, a cholesterol-lowering drug, is cleared from the body by being taken up into the liver via organic anion transporting polypeptides (OATPs) and then broken down by the enzyme CYP3A4. A clinical study using a microdose cocktail given to eight healthy volunteers showed that blocking OATPs with rifampicin increased atorvastatin's exposure 12-fold, while blocking CYP3A4 with itraconazole had no effect. This demonstrates that hepatic uptake via OATPs, not metabolism by CYP3A4, is the dominant process for eliminating atorvastatin at a subtherapeutic dose.
Microdosing studies help identify early pharmacokinetic properties of drugs in humans, but nonlinearity between microdose and therapeutic dose due to saturation of metabolic enzymes and transporters is a concern. In healthy subjects, verapamil and quinidine, substrates of MDR1 and CYP3A4, showed dose-dependent pharmacokinetics. Dose-normalized AUC values increased 2.6-fold for quinidine and 2.3-fold for verapamil at therapeutic doses compared to microdoses, suggesting saturation of MDR1 and/or CYP3A4 in the small intestine causes nonlinearity.