Relative Contributions of Presystemic and Systemic Peptidases to Oral Exposure of a Novel Metabotropic Glutamate 2/3 Receptor Agonist (LY404039) After Oral Administration of Prodrug Pomaglumetad Methionil (LY2140023)

Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia

“…Since MGS0008 was not metabolized in the preclinical species, the large species differences in oral bioavailability might be due to differences in the rates of its gastrointestinal absorption, such as transporter‐mediated uptake in rats. Species differences in oral bioavailability have also been reported for LY354740 (high in dogs and low in humans) and LY404039 (high in rats and low in humans) . MGS0008, which has a fluorine‐substituted structure of LY354740 at the C3 position, is also likely to exhibit low oral bioavailability in humans.…”

“…The mGlu2/3 receptor agonists, LY404039 and LY354740 (Figure ), are rigid glutamate analogs and exhibited poor gastrointestinal absorption in humans (oral bioavailability of 3‐6%), probably because of poor membrane permeability arising from their hydrophilic properties. Accordingly, a prodrug approach was inevitable to improve their oral bioavailability …”

“…To improve the gastrointestinal absorption of hydrophilic compounds, transportable prodrugs or ester‐based lipophilic prodrugs are generally worth being developed . Both LY544344 (a prodrug of LY354740) and LY2140023 (Figure ) were transportable prodrugs designed to be absorbed via intestinal peptide transporter 1 and have indeed improved oral bioavailability in humans, compared with their parent compounds . Although the transportable prodrug approach was successful, systemic exposure to the prodrug was still observed for LY2140023, accounting for roughly 30% of its parent compound in humans and 15% of circulating radioactivity in monkeys .…”

Approaches to intravenous clinical pharmacokinetics: Recent developments with isotopic microtracers

“…Microtracer studies designed to obtain intravenous PK conducted to date published in the peer‐reviewed literature are summarized in Tables and . Over time, the design of the microtracer study as evolved so that the intravenous dose is administered typically as an infusion to coincide with the t max of the extravascular dose.…”

“…Microtracer studies designed to obtain intravenous PK conducted to date published in the peer-reviewed literature are summarized in Tables 1a 30,43,[49][50][51] and 1b. 41,[52][53][54][55][56][57][58][59] Over time, the design of the microtracer study as evolved so that the intravenous dose is administered typically as an infusion to coincide with the t max of the extravascular dose. This adjustment of the study design accounts for the absorption phase of the extravascular dose, in which some nonlinearity in the PK might be apparent because of the system not being in equilibrium between dose routes.…”