Citation

Roberts DM, Dawson AH, Senarathna L, Mohamed F, Cheng R, Eaglesham G, Buckley NA. Toxicol. Lett. 2011; 201(3): 270-276.

Copyright

(Copyright © 2011, Elsevier Publishing)

DOI

10.1016/j.toxlet.2011.01.011

PMID

21256202

PMCID

PMC3060340

Abstract

Human data on protein binding and dose-dependent changes in toxicokinetics for MCPA are very limited. 128 blood samples were obtained in 49 patients with acute MCPA poisoning and total and unbound concentrations of MCPA were determined. The Scatchard plot was biphasic suggesting protein binding to two sites. The free MCPA concentration increased when the total concentration exceeded 239mg/L (95% confidence interval 198-274mg/L). Nonlinear regression using a two-site binding hyperbola model estimated saturation of the high affinity binding site at 115mg/L (95%CI 0-304). Further analyses using global fitting of serial data and adjusting for the concentration of albumin predicted similar concentrations for saturable binding (184mg/L and 167mg/L, respectively) without narrowing the 95%CI. In 25 patients, the plasma concentration-time curves for both bound and unbound MCPA were approximately log-linear which may suggest first order elimination, although sampling was infrequent so zero order elimination cannot be excluded. Using a cut-off concentration of 200mg/L, the half-life of MCPA at higher concentrations was 25.5h (95%CI 15.0-83.0h; n=16 patients) compared to 16.8h (95%CI 13.6-22.2h; n=10 patients) at lower concentrations. MCPA is subject to saturable protein binding but the influence on half-life appears marginal.

Language: en

Keywords

Humans; Adult; Female; Male; Young Adult; Survival; Suicide, Attempted; Algorithms; Regression Analysis; Renal Dialysis; Half-Life; Acute Disease; Dose-Response Relationship, Drug; Herbicides; Albumins; Nonlinear Dynamics; Protein Binding; 2-Methyl-4-chlorophenoxyacetic Acid; Ultrafiltration; Ultracentrifugation