In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1.

Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with Km value of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter.

Pharmacokinetics of radiolabelled quinlukast in rats.

Pharmacokinetics together with in vivo metabolism and elimination of quinlukast, a potential anti-asthmatic and anti-inflammatory drug, were designed in rats. For this purpose, bile duct cannulated rats and an in situ perfused rat liver preparation were employed. 3H-radiolabelled compound was administered i.v. or loaded to the perfusion medium, respectively. Quinlukast represented the main form of radioactivity determined in plasma; in comparison with the parent drug metabolites were present in lower levels in the systemic circulation. The pharmacokinetic parameters related to the whole animal were calculated from quinlukast rat plasma concentration-time course. The distribution of quinlukast in the body was relatively fast (distribution half-life was approx. 6 min), the elimination half-life exceeded 2h. Binding of quinlukast to rat plasma proteins was very high (approx. 99.7%) and this binding influenced distribution volumes of quinlukast. Both the volume of the central compartment and the volume at a steady state were approx. 115 and 430 ml, respectively. The experiments showed that the biliary clearance was the major route of elimination of this compound from the systemic circulation of rats. In agreement with the determined elimination half-life approx. 42% of the radioactivity was found in the bile, with <0.5% appearing in the urine. The majority of the eliminated radioactivity in the bile was in the form of polar metabolites; only a small part of the parent compound was determined. Two hours after intravenous administration, polar metabolites - but no parent drug - were detected in the urine.

High-performance chromatographic assay for the sulphoxide metabolite of 2'-deoxy-3'-thiacytidine in human urine.

A high-performance liquid chromatographic method is described for the determination in human urine of GI138870X, the sulphoxide metabolite of a novel dideoxynucleoside analogue, 2'-deoxy-3'-thiacytidine (lamivudine). GI138870X was extracted from human urine using Empore SDB RPS solid-phase extraction disks prior to reversed-phase chromatography with UV detection. The method has shown to be valid over the concentration range 0.5-100 micrograms/ml using a 0.5-ml sample volume.