This is the first description of the toxicokinetics of MCPA in a series of patients with intentional self-poisoning. MCPA displays two-site protein binding with saturation of the higher affinity binding site at a concentration less than 200 mg/L. This is within the concentration range typically observed in patients Ponatinib with acute poisoning, which can exceed 1000 mg/L (e.g. Fig. 6). When the concentration of MCPA exceeds the point of

saturation, the free concentration increases rapidly and it is anticipated that MCPA will more readily distribute from the central compartment. The apparent elimination half-life at higher concentrations was 25.5 h which is slightly prolonged compared to the terminal phase of 16.8 h although the 95% confidence intervals of both estimations were wide. This long elimination half-life may contribute to the prolonged duration of poisoning observed in cases of self-poisoning, and slow elimination of MCPA may contribute to death. Therefore, more research is needed into the extent to which techniques for enhanced elimination, including urinary alkalinisation and haemodialysis, increase clearance and decrease the free concentration of MCPA. The chlorophenoxy herbicides MCPA and 2,4-D display similar kinetic properties (Arnold and Beasley, 1989 and Timchalk, 2004).

Case reports of human self-poisoning have attributed a change in the apparent elimination half life of chlorophenoxy herbicides to treatment Nutlin-3a solubility dmso with urinary alkalinisation/diuresis (Flanagan et al., 1990, Friesen et al., 1990, Prescott et al., 1979 and Schmoldt et N-acetylglucosamine-1-phosphate transferase al., 1997). On review of these cases it appears that the change in the apparent elimination half-life occurred when the concentration was approximately 150–300 mg/L, similar to Fig. 1. This is similar to the MCPA concentration where protein binding to the high affinity site appeared to saturate in our study (Fig. 5a–c) and also in rat studies (Roberts and Buckley, 2007a). Therefore, it is possible that the change in the apparent elimination half-life in Fig. 1 may have related in-part to the concentration-dependent change in toxicokinetics

observed in our patients and in rat studies. Regardless of the method employed, it is noted that the affinity of the first binding site for MCPA is extremely high and that it is saturated when the MCPA concentration is less than 200 mg/L (Fig. 5a–c). This confirms ex vivo studies that demonstrated the importance of albumin for MCPA–protein binding ( Roberts and Buckley, 2007a). Given an albumin concentration of approximately 600 μM, if MCPA binds to albumin in a ratio of 1:1 then the binding sites are expected to be saturated at a concentration of 120 mg/L. We did not have sufficient high concentration samples to determine confidently if the second lower affinity site is potentially saturable with large exposures. The pKa of MCPA is 3.