Preclinical and clinical evidence for the collaborative transport and renal secretion of an oxazolidinone antibiotic by organic anion transporter 3 (OAT3/SLC22A8) and multidrug and toxin extrusion protein 1 (MATE1/SLC47A1).
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; K(m) = 44 +/- 5 microM) and human multidrug and toxin extrusion protein 1 (hMATE1; K(m) = 340 +/- 55 microM). 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.
Departments of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Pfizer Inc., St. Louis, Missouri, USA. yurong.lai@pfizer.com
Yurong
Y
Lai
Kathleen E
KE
Sampson
Larissa M
LM
Balogh
Timothy G
TG
Brayman
Steven R
SR
Cox
Wade J
WJ
Adams
Vikas
V
Kumar
Jeffrey C
JC
Stevens
D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002927:Cimetidine / Q000494:pharmacology; D003499:Cyclic S-Oxides / Q000378:metabolism* / Q000493:pharmacokinetics; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006801:Humans; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D023303:Oxazolidinones / Q000378:metabolism* / Q000493:pharmacokinetics; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012076:Renal Agents / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D003499:Cyclic S-Oxides; D006635:Histamine H2 Antagonists; C552257:N-((3-(4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D023303:Oxazolidinones; D012076:Renal Agents; C521869:SLC47A1 protein, human; C114338:organic anion transport protein 3; D002927:Cimetidine; D011339:Probenecid