In vivo kinetic analysis of covalent binding between N-acetyl-L-cysteine and plasma protein through the formation of mixed disulfide in rats.
OBJECTIVE
This investigation was undertaken to study the relationship between plasma drug clearance and covalent protein-binding kinetics of N-acetyl-L-cysteine (NAC).


METHODS
NAC was intravenously administered to rats via a bolus injection or continuous infusion. Plasma concentrations of protein-unbound and total NAC were analyzed using a compartment model, taking into consideration of the protein binding process, and the apparent first-order binding and dissociation rate constants (kon and koff) were obtained.


RESULTS
Plasma total NAC after a bolus injection showed biphasic elimination with an inflection point at 1 hr. After 1 hr, NAC was largely present in the covalent protein-bound form. During the steady state of the infusion, approximately 30%-40% of plasma NAC bound with protein covalently. The kon, koff, and the elimination rate constant of protein-unbound drug (ke) were 0.23, 0.57, and 4.3 hr(-1). The dissociation half-life of NAC from protein estimated from koff was in agreement with the elimination half-life of plasma total NAC. This suggests that the dissociation of NAC from protein rate-limited the drug elimination in plasma (koff < ke).


CONCLUSIONS
We demonstrated that plasma total drug clearance is kinetically limited by covalent protein binding. The compartmental model described here is useful for analyzing its kinetics in vivo.
Harada
Daisuke
D
Naruto Research Institute, Otsuka Pharmaceutical Factory, Inc., Tokushima, Japan. haradada@otsukakj.co.jp
Naito
Shinsaku
S
Hiraoka
Isao
I
Otagiri
Masaki
M
D000111:Acetylcysteine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D001798:Blood Proteins; D000111:Acetylcysteine