Abstract

Aim: Purpose of the study was to develop a PBPK model for amoxicillin incorporating saturable transport processes affecting the drug’s absorption and distribution.

Methods: Amoxicillin absorption and pharmacokinetics were simulated using GastroPlus™ 8.0 (Simulations Plus, Inc., Lancaster, CA). The program ’s Advanced Compartmental Absorption and Transit (ACAT™) model described the passive and carrier-mediated absorption of the drug, while pharmacokinetics were simulated with its PBPKPlus™ module. Human organ weights, volumes, and blood perfusion rates were generated by the program’s internal Population Estimates for Age-Related (PEAR) Physiology™ module. Individual tissues were represented as permeability limited (diffusion-limited) models. Drug partitioning between plasma and extracellular tissue space accounted for drug binding to plasma proteins and extracellular tissue proteins [1]. Drug uptake into cells was modeled by passive diffusion, as well as carrier-mediated (saturable) transport in tissues expressing PepT1/PepT2 and MRP4 transporters (small intestine, kidney, liver, brain). Relative transporter expression levels in kidney, liver and brain were based on published relative mRNA expression levels in these tissues [2]. An additional uptake transporter was added to kidney tissue to account for active renal secretion of amoxicillin. Passive renal secretion was estimated from fraction unbound in plasma and glomerular filtration rate. Distribution kinetic parameters as well as liver and renal (active secretion) contributions to amoxicillin’s clearance were fitted against plasma concentration-time (Cp-time) profiles and amounts secreted in urine after i.v. and p.o. administration of amoxicillin [3-5].

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

By Viera Lukacova, Michael B. Bolger, Walter S. Woltosz