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.
In 30 healthy volunteers matched for SLCO2B1 genotype, the effect of a genetic variant on the body's exposure to celiprolol depended on the dose. At a therapeutic dose (100 mg), people with two copies of the *3 variant had a lower average area under the concentration-time curve (AUC) of 775 ng·h/mL compared with 1097 ng·h/mL for those with one copy (*1/*3) and 1547 ng·h/mL for those with none (*1/*1). At a microdose (97.5 µg), these genotype differences disappeared. Dose-normalized AUC was much lower at the microdose, suggesting saturation of an efflux transporter at the therapeutic dose explains why the genetic effect only appears at that higher 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.