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Pharmaceutics 2017, 9(3), 34; https://doi.org/10.3390/pharmaceutics9030034

Comparative Pharmacokinetic Study for Linezolid and Two Novel Antibacterial Oxazolidinone Derivatives in Rabbits: Can Differences in the Pharmacokinetic Properties Explain the Discrepancies between Their In Vivo and In Vitro Antibacterial Activities?

1
Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait
Deceased.
*
Author to whom correspondence should be addressed.
Received: 26 July 2017 / Revised: 23 August 2017 / Accepted: 31 August 2017 / Published: 7 September 2017
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Abstract

This is a comparative pharmacokinetics study of linezolid (Lzd), and two novel oxazolidinone antibacterial agents—PH027 and PH051—in rabbits to determine if the discrepancy between the in vitro and in vivo activities of the novel compounds is due to pharmacokinetic factors. The pharmacokinetics after IV and oral administration, plasma protein binding and tissue distribution for the three compounds were compared. The elimination half-lives were 52.4 ± 6.3, 68.7 ± 12.1 and 175 ± 46.1 min for Lzd, PH027 and PH051, respectively. The oral bioavailability for Lzd, PH027 and PH051 administered as suspension were 38.7%, 22.1% and 4.73%, which increased significantly when administered as microemulsion to 51.7%, 72.9% and 13.9%. The plasma protein binding were 32–34%, 37–38% and 90–91% for Lzd, PH027 and PH051. The tissue distribution for PH027 and PH051 in all investigated tissues were higher than that for Lzd. It can be concluded that the lower bioavailability of PH027 and PH051 compared to Lzd when administered as suspension is the main cause of their lower in vivo activity, despite their comparable in vitro activity. Differences in the other pharmacokinetic characteristics cannot explain the lower in vivo activity. The in vivo activity of the novel compounds should be re-evaluated using formulations with good oral bioavailability. View Full-Text
Keywords: linezolid; oxazolidinone antibiotics; pharmacokinetics; renal excretion; bioavailability; tissue distribution; microemulsion linezolid; oxazolidinone antibiotics; pharmacokinetics; renal excretion; bioavailability; tissue distribution; microemulsion
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Hedaya, M.A.; Thomas, V.; Abdel-Hamid, M.E.; Kehinde, E.O.; Phillips, O.A. Comparative Pharmacokinetic Study for Linezolid and Two Novel Antibacterial Oxazolidinone Derivatives in Rabbits: Can Differences in the Pharmacokinetic Properties Explain the Discrepancies between Their In Vivo and In Vitro Antibacterial Activities? Pharmaceutics 2017, 9, 34.

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