Effect of dose escalation on the in vivo oral absorption and disposition of glycylsarcosine in wild-type and Pept1 knockout mice.

This study evaluated the in vivo absorption and disposition of glycylsarcosine (GlySar), after escalating oral doses, in wild-type and peptide transporter 1 (Pept1) knockout mice. [(3)H]GlySar was administered to mice at doses of 1, 10, 100, 1000, and 5000 nmol/g b.wt. Serial blood samples were obtained over 480 min, the plasma was harvested, and the area under the plasma concentration-time curve (AUC) was determined. It was observed that the GlySar AUC was 60, 45, and 30% lower in knockout than wild-type mice when evaluated over 2, 4, and 8 h, respectively (p < 0.01). Plasma levels of GlySar reached a plateau at 90 min in knockout mice and then rose to a second plateau at 240 min. In wild-type mice, the plasma levels rose continuously to reach a single plateau at 90 min. When partial AUC (0-120 min) was used as an indicator for rate of absorption, there was a 60% reduction in GlySar absorption rate in knockout mice compared with wild-type animals. Tissue distribution studies were also performed after 10 nmol/g oral doses of [(3)H]GlySar. When sampled 1 h after dosing, GlySar tissue concentrations were significantly lower in knockout versus wild-type mice and, with the exception of intestines, reflected differences in the systemic exposure of dipeptide between these two genotypes. Overall, PEPT1 ablation in mice resulted in significant reductions, in vivo, in the rate and extent of GlySar absorption. The AUC of GlySar was proportional to dose in both genotypes over 1 to 100 nmol/g, with minor decrements at the two highest doses.