Analysis of LK-157 in Plasma by LC–MS–MS: Application to Studies of Pharmacokinetics and Degradation Pathways in Rats and Dogs |
| |
Authors: | Petra Igličar Andrej Preželj Igor Locatelli Jurij Trontelj Samo Andrenšek Nataša Kovačić Uroš Urleb Aleš Mrhar |
| |
Affiliation: | 1. Lek Pharmaceuticals d.d., Verov?kova 57, 1000, Ljubljana, Slovenia 2. Faculty of Pharmacy, University of Ljubljana, A?ker?eva 7, 1000, Ljubljana, Slovenia 3. ERICo Velenje, Institute for Ecological Research, Koro?ka 58, 3322, Velenje, Slovenia
|
| |
Abstract: | Multiple-species plasma-stability testing and pharmacokinetic studies in rats and dogs were performed on LK-157, a novel 10-ethylidene tricyclic carbapenem and potent inactivator of β-lactamases of classes A, C, and D. An LC–MS–MS method was developed and validated for analysis of LK-157 in rat and dog plasma. Separation was achieved on a C18 column by gradient elution. The lower limit of quantification for LK-157 in plasma was 50 ng mL?1. Intra-day and inter-day precision were <12.5 and <11.8%, respectively. When degradation of LK-157 was assessed in buffer solutions and in rat, dog, and human plasma, the compound was found to be stable in pH 7.0–9.0 phosphate buffer for 24 h at room temperature, and in human plasma for 60 min at 37 °C. The stability of LK-157 was species-dependent. Results from study of in vitro metabolism showed that the enzymes liver cytochrome P450 and uridine diphosphate glycosyltransferase do not metabolize LK-157. LC–MS–MS was also successfully applied to a pharmacokinetic study. The pharmacokinetics of LK-157 after bolus intravenous administration (10 mg kg?1) to Wistar rats and Beagle dogs was described by a two-compartment pharmacokinetic model. Human pharmacokinetic data were extrapolated from dog pharmacokinetic data. The extrapolated human terminal-phase half-life of LK-157 was 2.3 h. Stability and pharmacokinetic data for LK-157 are in agreement with results for other inactivators of β-lactamases. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|