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Analysis of LK-157 in Plasma by LC–MS–MS: Application to Studies of Pharmacokinetics and Degradation Pathways in Rats and Dogs

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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.

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Acknowledgments

The authors would like to acknowledge a group of chemists from Drug Discovery (Lek d.d., Ljubljana, Slovenia) for preparing the LK-157 used in these studies. In addition, we would like to thank Andrej Kocijan for his assistance with the TOF experiments.

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Authors and Affiliations

  1. Lek Pharmaceuticals d.d., Verovškova 57, 1000, Ljubljana, Slovenia

    Petra Igličar, Andrej Preželj, Samo Andrenšek & Uroš Urleb

  2. Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia

    Igor Locatelli, Jurij Trontelj & Aleš Mrhar

  3. ERICo Velenje, Institute for Ecological Research, Koroška 58, 3322, Velenje, Slovenia

    Nataša Kovačić

Authors
  1. Petra Igličar
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  2. Andrej Preželj
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  3. Igor Locatelli
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  4. Jurij Trontelj
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  5. Samo Andrenšek
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  6. Nataša Kovačić
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  7. Uroš Urleb
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  8. Aleš Mrhar
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Correspondence to Petra Igličar.

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Igličar, P., Preželj, A., Locatelli, I. et al. Analysis of LK-157 in Plasma by LC–MS–MS: Application to Studies of Pharmacokinetics and Degradation Pathways in Rats and Dogs. Chroma 70, 1103–1112 (2009). https://doi.org/10.1365/s10337-009-1307-5

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