Importance of PEPT1 in the Absorption, Tissue Distribution and Disposition of Cefadroxil.

Abstract

Although PEPT1 is the most important pathway in the absorption of di- and tri-peptides in the small intestine, its in vivo relevance in the absorption, tissue distribution, and disposition of pharmacologically active compounds is still not well understood. Hence, we decided to study the role of PEPT1 in the following: 1) the intestinal permeability of cefadroxil, 2) the in vivo pharmacokinetics of cefadroxil, and finally 3) the in silico absorption and pharmacokinetics of cefadroxil using the advanced compartmental absorption and transit (ACAT) model built into Gastroplus®. Cefadroxil was chosen as a model drug to study PEPT1 because of its good metabolic stability and commercial availability as a radiolabeled compound. The findings show that PEPT1 was responsible for 90% of the effective permeability (Peff) of cefadroxil. PEPT1 transport of cefadroxil in the jejunum of wild-type mice had a Km of 3.8 mM and a Vmax of 4.75 nmol/cm2/s. Also, the Peff in the duodenum, jejunum, and ileum were significantly higher in wild-type than in PEPT1 knockout mice, but not in colon where the Peff was very low in both genotypes. After oral administration, the Cmax and AUC0-120 across all doses were lower in knockout mice than in wild-type animals. There was also an “apparent” linearity in the Cmax and AUC0-120 for both genotypes. However, the analysis of the intravenous data showed no difference in disposition between genotypes. The third specific aim was an effort to integrate the experimental results and to retrospectively model the absorption and pharmacokinetics of cefadroxil using an ACAT model. In the knockout mice, a good prediction of plasma concentration-time profiles was obtained for all doses studied. In the wild-type mice, the plasma concentration-time profiles for the lower doses were reproduced. The model predicts saturation of the intestinal PEPT1 at higher concentrations in wild-type mice that was not seen experimentally, probably due to a simultaneous saturation of the active tubular secretion and reabsorption, resulting in an apparent linearity of the plasma concentration-time profiles as a function of dose. A physiologically-based pharmacokinetic model will need to be developed to take into account the saturation in cefadroxil renal clearance.PHDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/96139/1/mmposada_1.pd