Probenecid, an organic anion transporter 1 and 3 inhibitor, increases plasma and brain exposure of N-acetylcysteine.
1. N-acetylcysteine (NAC) is being investigated as an antioxidant for several conditions including traumatic brain injury, but the mechanism by which it crosses membrane barriers is unknown. We have attempted to understand how the transporter inhibitor, probenecid, affects NAC pharmacokinetics and to evaluate the interaction of NAC with transporters. 2. Juvenile Sprague-Dawley rats were administered NAC alone or in combination with probenecid intraperitoneally. Plasma and brain samples were collected serially and NAC concentrations were measured. Transporter studies were conducted with human embryonic kidney-293 cells that overexpress organic anion transporter (OAT)1 or OAT3 and with human multi-drug resistance-associated protein (MRP)1 or MRP4 membrane vesicles. 3. NAC area under the curve was increased in plasma (1.65-fold) and brain (2.41-fold) by probenecid. The apparent plasma clearance was decreased by 65%. Time- and concentration-dependent NAC uptake that was inhibitable by probenecid was observed with OAT1 and OAT3. No uptake of NAC was observed with MRP1 or MRP4. 4. Our results indicate for the first time that NAC is substrate for OAT1 and OAT3 and that probenecid increases NAC plasma and brain exposure in vivo. These data provide insight regarding how NAC crosses biological barriers and suggest a promising therapeutic strategy to increase NAC exposure.
a Department of Pharmaceutical Sciences , and.
Fanuel T
FT
Hagos
b Department of Pharmacy and Therapeutics , Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , PA , USA.
Monica J
MJ
Daood
b Department of Pharmacy and Therapeutics , Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , PA , USA.
Jacob A
JA
Ocque
b Department of Pharmacy and Therapeutics , Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , PA , USA.
Thomas D
TD
Nolin
c Department of Critical Care Medicine and.|d Safar Center for Resuscitation Research , School of Medicine, University of Pittsburgh , Pittsburgh , PA , USA , and.|e Children's Hospital of Pittsburgh of UPMC , Pittsburgh , PA , USA.
Hulya
H
Bayir
a Department of Pharmaceutical Sciences , and.
Samuel M
SM
Poloyac
c Department of Critical Care Medicine and.|d Safar Center for Resuscitation Research , School of Medicine, University of Pittsburgh , Pittsburgh , PA , USA , and.|e Children's Hospital of Pittsburgh of UPMC , Pittsburgh , PA , USA.
Patrick M
PM
Kochanek
c Department of Critical Care Medicine and.|d Safar Center for Resuscitation Research , School of Medicine, University of Pittsburgh , Pittsburgh , PA , USA , and.|e Children's Hospital of Pittsburgh of UPMC , Pittsburgh , PA , USA.
Robert S B
RS
Clark
b Department of Pharmacy and Therapeutics , Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , PA , USA.
Philip E
PE
Empey
D000111:Acetylcysteine / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D004347:Drug Interactions; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D010949:Plasma / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D027361:Organic Anion Transporters; D011339:Probenecid; D000111:Acetylcysteine
Antioxidant; inhibitor; n-acetylcysteine; organic anion tranporter; pharmacokinetics; probenecid; transporter