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Toxicokinetics, including saturable protein binding, of 4-chloro-2-methyl phenoxyacetic acid (MCPA) in patients with acute poisoning |
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| Authors: | Roberts Darren M Dawson Andrew H Senarathna Lalith Mohamed Fahim Cheng Ron Eaglesham Geoffrey Buckley Nick A |
| Affiliation: | a South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka1 b Burns, Trauma and Critical Care Research Centre, Royal Brisbane and Women''s Hospital, University of Queensland, Brisbane, Queensland, Australia c Professorial Medicine Unit, POWH Clinical School, University of New South Wales, Randwick, New South Wales, Australia d New South Wales Poisons Information Centre, The Children''s Hospital, Westmead, New South Wales, Australia e Organic Chemistry, Queensland Health Forensic and Scientific Services, Brisbane, Queensland, Australia |
| 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 239 mg/L (95% confidence interval 198-274 mg/L). Nonlinear regression using a two-site binding hyperbola model estimated saturation of the high affinity binding site at 115 mg/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 (184 mg/L and 167 mg/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 200 mg/L, the half-life of MCPA at higher concentrations was 25.5 h (95%CI 15.0-83.0 h; n = 16 patients) compared to 16.8 h (95%CI 13.6-22.2 h; n = 10 patients) at lower concentrations. MCPA is subject to saturable protein binding but the influence on half-life appears marginal. |
| Keywords: | MCPA, 4-chloro-2-methylphenoxyacetic acid 2,4-D, 2,4-dichlorophenoxyacetic acid t1/2, apparent elimination half-life Cu, free (unbound) plasma concentration Kdi, affinity constant of binding at the ith site Bmaxi, maximum density (concentration of saturation) of binding at the ith site Ci, initial concentration Ct, concentration after time t k, elimination rate constant LOD, limit of detection LOR, limit of reporting Tmax, time of the maximum plasma concentration IQR, interquartile range Koc, octanol solubility coefficient pKa, acid dissociation constant CL, clearance Vd, volume of distribution |
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