Importance of Peptide transporter 2 on the cerebrospinal fluid efflux kinetics of glycylsarcosine characterized by nonlinear mixed effects modeling.
Pharm Res
; 30(5): 1423-34, 2013 May.
Article
em En
| MEDLINE
| ID: mdl-23371515
ABSTRACT
PURPOSE:
To develop a population pharmacokinetic model to quantitate the distribution kinetics of glycylsarcosine (GlySar), a substrate of peptide transporter 2 (PEPT2), in blood, CSF and kidney in wild-type and PEPT2 knockout mice.METHODS:
A stepwise compartment modeling approach was performed to describe the concentration profiles of GlySar in blood, CSF, and kidney simultaneously using nonlinear mixed effects modeling (NONMEM). The final model was selected based on the likelihood ratio test and graphical goodness-of-fit.RESULTS:
The profiles of GlySar in blood, CSF, and kidney were best described by a four-compartment model. The estimated systemic elimination clearance, volume of distribution in the central and peripheral compartments were 0.236 vs 0.449 ml/min, 3.79 vs 4.75 ml, and 5.75 vs 9.18 ml for wild-type versus knockout mice. Total CSF efflux clearance was 4.3 fold higher for wild-type compared to knockout mice. NONMEM parameter estimates indicated that 77% of CSF efflux clearance was mediated by PEPT2 and the remaining 23% was mediated by the diffusional and bulk clearances.CONCLUSIONS:
Due to the availability of PEPT2 knockout mice, we were able to quantitatively determine the significance of PEPT2 in the efflux kinetics of GlySar at the blood-cerebrospinal fluid barrier.
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MEDLINE
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Simportadores
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Dipeptídeos
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article