Abstract
N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (PNU-288034), an oxazolidinone antibiotic, was terminated in phase I clinical development because of insufficient exposure. Analysis of the drug pharmacokinetic and elimination profiles suggested that PNU-288034 undergoes extensive renal secretion in humans. The compound was well absorbed and exhibited approximately linear pharmacokinetics in the oral dose range of 100 to 1000 mg in human. PNU-288034 was metabolically stable in liver microsomes across species, and unchanged drug was cleared in the urine by an apparent active renal secretion process in rat and monkey (two to four times glomerular filtration rate) but not dog. In vitro studies conducted to characterize the transporters involved demonstrated PNU-288034 uptake by human organic anion transporter 3 (OAT3; Km = 44 ± 5 μM) and human multidrug and toxin extrusion protein 1 (hMATE1; Km = 340 ± 55 μM). The compound was also transported by multidrug resistance P-glycoprotein and breast cancer resistance protein. In contrast, human organic cation transporter 2, human OAT1, and hMATE2-K did not transport PNU-288034. Coadministration of PNU-288034 and the OAT3 inhibitor probenecid significantly increased PNU-288034 plasma area under the curve (170%) and reduced both plasma and renal clearance in monkey. Coadministration of PNU-288034 and cimetidine, a MATE1 inhibitor, also reduced plasma clearance in rat to a rate comparable with probenecid coadministration. Collectively, our results demonstrated a strong in vitro–in vivo correlation for active renal secretion coordinated through the vectorial transport process of OAT3 and MATE1, which ultimately resulted in limiting the systemic exposure of PNU-288034.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.170753.
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ABBREVIATIONS:
- PNU-288034
- N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide
- P-gp
- P-glycoprotein
- BCRP
- breast cancer resistance protein
- OCT
- organic cation transporter
- OAT
- organic anion transporter
- hOAT
- human OAT
- MATE
- multidrug and toxin extrusion protein
- hMATE
- human MATE
- GFR
- glomerular filtration rate
- Cmax
- maximum concentration
- Tmax
- time to Cmax
- CL
- clearance
- AUC
- area under the curve
- DDI
- drug–drug interaction
- WT
- wild type
- LC-MS/MS
- liquid chromatography/tandem mass spectrometry
- ACN
- acetonitrile
- SVC
- superior vena cava
- HEK
- human embryonic kidney
- HBSS
- Hanks' balanced salt solution
- MEM
- minimum essential medium
- FBS
- fetal bovine serum
- MDCK
- Madin-Darby canine kidney
- Papp
- apparent permeability
- MRT
- mean residence time
- PNU-100766
- (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
- Received May 26, 2010.
- Accepted June 1, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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