Importance of Peptide Transporter 2 on the Cerebrospinal Fluid Efflux Kinetics of Glycylsarcosine Characterized by Nonlinear Mixed Effects Modeling

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.

Interaction Between Sex and Organic Anion‐Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib‐N‐Oxide and Regorafenib‐Glucuronide in Mice

“…The population pharmacokinetics of regorafenib and its metabolites were analyzed in a stepwise manner. Similar methods involving transporter‐mediated pharmacokinetic profiles have been applied to levofloxacin and glycylsarcosine . All models were created using the first‐order conditional estimation method, and the subroutine ADVAN6 was used to describe all model kinetics process, which included interindividual and residual variabilities.…”

Semi-Mechanistic Population Pharmacokinetic Modeling of L-Histidine Disposition and Brain Uptake in Wildtype and Pht1 Null Mice

“…Proton-coupled oligopeptide transporters (POTs) are responsible for translocating various di/tripeptides and peptidomimetics across biological membranes (1,2). They have a significant influence on the pharmacokinetics (PK) and pharmacodynamics (PD) of their substrates (3–5). To date, four mammalian members of the POT superfamily have been identified, including peptide transporter 1 (PEPT1) and 2 (PEPT2), and peptide/histidine transporter 1 (PHT1) and 2 (PHT2).…”

“…To date, four mammalian members of the POT superfamily have been identified, including peptide transporter 1 (PEPT1) and 2 (PEPT2), and peptide/histidine transporter 1 (PHT1) and 2 (PHT2). Unlike PEPT1 and PEPT2, which have been well studied through experiments and modeling approaches (3–5), there is limited information available for PHT1, especially regarding the impact of PHT1 on the PK of its substrates.…”

Population pharmacokinetic modeling of cefadroxil renal transport in wild-type andPept2knockout mice

“…Thus, a nonlinear mixed effect modeling (NONMEM) approach can be utilized to address different sources of variability and allow the estimation of all the kinetic parameters of interest (i.e., nonlinear and/or linear pharmacokinetic parameters) (Beal and Sheiner, 1984). This method has been employed to analyze transporter-mediated nonlinear pharmacokinetics of several compounds including cefuroxime, glycylsarcosine and levofloxacin (Ruiz-Carretero et al, 2004; Huh et al, 2013; Hurtado et al, 2014). Hence, the purpose of this study was to develop a population pharmacokinetic model of cefadroxil in wildtype and Pept2 knockout mice using the NONMEM approach.…”