Toxicokinetics, including saturable protein binding, of 4-chloro-2-methyl phenoxyacetic acid (MCPA) in patients with acute poisoning.
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.
South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka. darren1@gmail.com
Darren M
DM
Roberts
Andrew H
AH
Dawson
Lalith
L
Senarathna
Fahim
F
Mohamed
Ron
R
Cheng
Geoffrey
G
Eaglesham
Nick A
NA
Buckley
D008456:2-Methyl-4-chlorophenoxyacetic Acid / Q000493:pharmacokinetics* / Q000506:poisoning* / Q000633:toxicity; D000208:Acute Disease; D000328:Adult; D000418:Albumins / Q000378:metabolism; D000465:Algorithms; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006540:Herbicides / Q000493:pharmacokinetics* / Q000506:poisoning* / Q000633:toxicity; D006801:Humans; D008297:Male; D017711:Nonlinear Dynamics; D011485:Protein Binding; D012044:Regression Analysis; D006435:Renal Dialysis; D013406:Suicide, Attempted; D013534:Survival; D014461:Ultracentrifugation; D014462:Ultrafiltration; D055815:Young Adult
D000418:Albumins; D006540:Herbicides; D008456:2-Methyl-4-chlorophenoxyacetic Acid
Life Sci. 1981 Aug 3;29(5):427-43
6116137
Food Cosmet Toxicol. 1976 Jan;14(1):19-23
3460
J Toxicol Clin Toxicol. 1997;35(4):405-8
9204102
Arch Toxicol. 1983 Dec;54(4):267-73
6667117
Clin Pharmacokinet. 2007;46(11):897-939
17922558
Food Cosmet Toxicol. 1977 Aug;15(4):297-301
590891
Biochem Pharmacol. 1989 Jul 1;38(13):2053-60
2544182
Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005488
17253558
Chemosphere. 2003 Apr;51(1):47-54
12586155
J Appl Toxicol. 1989 Aug;9(4):255-8
2778260
Vet Hum Toxicol. 1989 Apr;31(2):121-5
2648672
Toxicology. 2004 Jul 15;200(1):1-19
15158559
J Toxicol Clin Toxicol. 2004;42(1):1-26
15083932
Life Sci. 1998;63(26):2343-51
9877224
Biochem Pharmacol. 1982 Jan 15;31(2):149-55
7059358
Food Chem Toxicol. 2004 Jan;42(1):115-25
14630135
Br J Clin Pharmacol. 1979 Jan;7(1):111-6
32900
Clin Chem. 1974 May;20(5):615-6
4826961
Ann Emerg Med. 2005 Sep;46(3):275-84
16126140
Drug Saf. 1990 Mar-Apr;5(2):155-9
2322426
Scand J Work Environ Health. 1977 Jun;3(2):100-3
882857
Toxicol Rev. 2004;23(2):65-73
15578861
Lancet. 1990 Feb 24;335(8687):454-8
1968179