PBPK Modeling of Erythromycin Absorption and Disposition Mediated by Transporters in Humans

Conference: AAPS
Division: PBPK


Purpose: Erythromycin, a macrolide antibiotic, is cleared primarily by cytochrome P450-3A4 metabolism. Its uptake into enterocytes and hepatocytes is mediated by organic anion transporter (OAT) and organic anion transporting polypeptides (OATPs), respectively. Erythromycin is actively secreted into the gastrointestinal lumen, where it is partially degraded, and into the bile by P-glycoprotein (P-gp ), and it undergoes enterohepatic recirculation. The purpose of this study was to build a comprehensive and mechanistic Physiologically Based Pharmacokinetic (PBPK) model of erythromycin incorporating all of the above-mentioned processes.

Methods: A mechanistic PBPK model that describes the pharrnacokinetics of erythromycin in healthy humans was developed with GastroPlus™ (Simulations Plus, Inc.) using literature plasma concentration-time (Cp-time) profiles after intravenous and oral administration of doses ranging from 125 to 1000 mg [I, 2]. Human organ weights, volumes, and blood perfusion rates were generated by the program’s internal Population Estimates for Age-Related (PEAR) Physiology™. Different physicochemical and biochemical parameters that predict absorption and distribution were obtained from literature or using ADMET Predictor™ (Simulations Plus, Inc.). Tissue:plasma partition coefficients (Kps) were calculated using Lukacova method [3]. Metabolic clearance of erythromycin was parameterized from in vitro measurements of erythromycin N-demethylation in human liver microsomes. Renal clearance rate reported in the literature was used in the model [I]. Gastrointestinal distribution of P-gp and OAT was derived from experimental data [5, 6]. A single set of V max and Km values each for OAT, P-gp and OA TP were fitted to describe the intravenous and oral profiles at different dose levels.

American Association of Pharmaceutical Scientists (AAPS), October 14-18, 2012, Chicago, IL

By Harisha Atluri, Siladitya Ray Chaudhuri, Grazyna Fraczkiewicz, Viera Lukacova, Michael B. Bolger, and Walter S. Woltosz