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Impact of Genetic Knockout of PEPT2 on the Pharmacokinetics, Renal Tubular Reabsorption, and Brain Penetration of Cefadroxil in Transgenic Mice
Author(s) -
Shen Hong,
Ocheltree Scott M.,
Hu Yongjun,
Keep Richard F.,
Smith David E.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.184.5
Subject(s) - cefadroxil , pharmacokinetics , reabsorption , pharmacology , chemistry , renal physiology , kidney , medicine , bolus (digestion) , endocrinology , biology , antibiotics , cephalosporin , biochemistry
In this study, the disposition of the antibiotic cefadroxil was evaluated in the body, particularly the kidney and brain, of wild‐type and PEPT2 null mice after intravenous bolus administrations of cefadroxil (i.e., at 1, 12.5, 50, and 100 nmol/g body weight). Cefadroxil plasma pharmacokinetics were clearly nonlinear over the dose range studied (1–100 nmol/g), which reflected both saturable renal tubular secretion and reabsorption of the antibiotic. PEPT2 null mice exhibited a 3‐fold greater total clearance and 3‐fold lower systemic concentrations of drug compared with wild‐type animals after an intravenous bolus dose of 1 nmol/g cefadroxil. Renal clearance studies further demonstrated that the renal reabsorption of cefadroxil was almost completely abolished in PEPT2 null versus wild‐type mice (3% versus 70%, p < 0.001). Of the 70% of cefadroxil reabsorbed in wild‐type mice, PEPT2 accounted for 95% and PEPT1 accounted for 5% of reabsorbed substrate. Tissue distribution studies indicated that PEPT2 had a dramatic effect on cefadroxil tissue exposure, especially in brain where the cerebrospinal fluid (CSF)‐to‐blood concentration ratio of cefadroxil was 6‐fold greater in PEPT2 null mice compared with wild‐type animals. These findings demonstrate that renal PEPT2 is almost entirely responsible for the reabsorption of cefadroxil in kidney and that choroid plexus PEPT2 limits the exposure of cefadroxil and probably other aminocephalosporins in CSF.