The Effect of Cytochrome P450 and Organic Anion Transporter Polypeptide on Macrolides–Atorvastatin Drug Interaction

Cytochrome P450 (CYP3A4) enzymes and organic anion-transporting polypeptides (OATPs) are critical in drug pharmacokinetics. Fifteen rabbits were divided into three groups: the atorvastatin group received a single oral dose of atorvastatin (0.86 mg/kg B.W.); the clarithromycin-atorvastatin group received a single oral dose of clarithromycin (43.7 mg/kg B.W.), followed by atorvastatin (0.86 mg/kg B.W.) 30 minutes later; and the azithromycin-atorvastatin group received a similar dosing protocol with azithromycin instead of clarithromycin. High-performance liquid chromatography (HPLC) measured atorvastatin concentrations in hyperlipidemic rabbit serum, while ELISA assessed macrolides’ CYP3A4 and OATP inhibition potential. Coadministration of clarithromycin significantly increased atorvastatin’s area under the curve (AUC) by 2.74-fold, compared to a slight increase of 1.11-fold with azithromycin. CYP3A4 inhibition was higher in the clarithromycin group (1.67-fold in the liver, 1.50-fold in the intestine) than the azithromycin group (1.64-fold in the liver, 1.17-fold in the intestine). Similarly, OATP inhibition in serum, liver, and intestine was greater in the clarithromycin group (1.4-fold, 1.5-fold, and 1.9-fold, respectively) compared to the azithromycin group (1.1-fold, 1.2-fold, and 1.1-fold, respectively). The results suggest that atorvastatin does not interact with azithromycin, while clarithromycin strongly interacts with it, indicating potential pharmacokinetic concerns in coadministration.