Mechanisms of cefadroxil uptake in the choroid plexus: studies in wild-type and PEPT2 knockout mice.

Article Details

Citation

Copy to clipboard

Ocheltree SM, Shen H, Hu Y, Xiang J, Keep RF, Smith DE

Mechanisms of cefadroxil uptake in the choroid plexus: studies in wild-type and PEPT2 knockout mice.

J Pharmacol Exp Ther. 2004 Feb;308(2):462-7. Epub 2003 Nov 4.

PubMed ID

14600253 [ View in PubMed

]

Abstract

The choroid plexus uptake of [(3)H]cefadroxil was studied in peptide transporter 2 (PEPT2) wild-type and null mice as a function of temperature, transport inhibitors, pH, and saturability. At normal pH (7.4) and temperature (37 degrees C), the uptake of 1 microM cefadroxil was reduced by 83% in PEPT2(-/-) mice as compared with PEPT2(+/+) mice (p < 0.001). A further reduction was achieved in null animals by reducing the temperature to 4 degrees C, or by adding saturating concentrations of unlabeled cefadroxil or p-aminohippurate (p < 0.05). Glycylsarcosine coadministration could inhibit the uptake of cefadroxil in PEPT2(+/+) mice (p < 0.01) but not PEPT2(-/-) mice. Although a proton-stimulated uptake of cefadroxil was demonstrated in PEPT2(+/+) mice (pH 6.5 versus pH 7.4; p < 0.01), no pH dependence was observed in PEPT2(-/-) mice. Kinetic parameters for cefadroxil (without p-aminohippurate) in wild-type mice were: V(max) = 5.4 pmol/mg/min, K(m) = 34 microM, and K(d) = 0.0069 microl/mg/min; in the presence of p-aminohippurate, the parameters were: V(max) = 4.1 pmol/mg/min, K(m) = 27 microM, and K(d) = 0.0064 microl/mg/min. In null animals, the kinetic parameters of cefadroxil (without p-aminohippurate) were: V(max) = 2.7 pmol/mg/min, K(m) = 110 microM, and K(d) = 0.0084 microl/mg/min; in the presence of p-aminohippurate, only a K(d) = 0.010 microl/mg/min was observed. Based on kinetic and inhibitor analyses, it was determined that (under linear conditions), 80 to 85% of cefadroxil's uptake in choroid plexus is mediated by PEPT2, 10 to 15% by organic anion transporter(s), and 5% by nonspecific mechanisms. These findings demonstrate that PEPT2 is the primary transporter responsible for cefadroxil uptake in the choroid plexus. Moreover, the data suggest a role for PEPT2 in the clearance of peptidomimetics from cerebrospinal fluid.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cefadroxil	Penicillin-binding protein 2B	Protein	Streptococcus pneumoniae (strain ATCC BAA-255 / R6)	Yes	Inhibitor	Details
Ubenimex	Bacterial leucyl aminopeptidase	Protein	Vibrio proteolyticus	Unknown	Not Available	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Cefadroxil	Solute carrier family 15 member 2	Protein	Humans	Unknown	Inhibitor	Details