This is reflected in the octanol solubility coefficient (Koc) which is a measure of lipophilicity. The Koc of MCPA is 1.0 at pH 6 and higher, but the Koc increases to 5.2 at pH 5 and then 45.6 at pH 4 (25 °C) ( SciFinder, 2010). In vitro studies have confirmed enhanced cytotoxicity of chlorophenoxy compounds in an acidic medium, presumably due to an increase in cell penetration ( Cabral et al., 2003). Therefore, urinary and potentially plasma alkalinisation in patients is likely to decrease the rate and extent of distribution due to ion-trapping. Renal elimination is the most important route of clearance for MCPA (Fjeldstad
and Wannag, 1977 and Kolmodin-Hedman OSI744 et al., 1983) but hepatic clearance may also contribute since glucuronidated metabolites
are detected in the urine (Kolmodin-Hedman et al., 1983). MCPA is filtered, secreted and reabsorbed in the nephron and the extent of this varies between animal species, notably the rat and dog (Timchalk, 2004). Renal clearance also varies with hydration due to changes in urine flow (Proudfoot et al., 2004). With high MCPA exposures there is nonlinear renal clearance which may be due to saturation of Osimertinib datasheet active excretion (e.g., the renal organic anion transporting polypeptide) or direct nephrotoxicity (Koschier and Berndt, 1977, Pritchard et al., 1982 and van Ravenzwaay et al., 2004). Penicillin may decrease MCPA clearance by competing for active secretion, as noted in rats (Braunlich et al., 1989); this antibiotic was not administered to the patient who died in this series. Nephrotoxicity in acute MCPA poisoning has been reported previously (Roberts et al., 2005) and may have contributed to the death of one of our patients given the progressive increase in creatinine (Fig. 3) and the very
long elimination half-life. Interpretation of elimination half-life is complex because it is a secondary kinetic parameter that depends on clearance (CL) and volume of distribution (Vd) which are related by half-life (t1/2), where t1/2 = 0.693 · Vd/CL. Further, the true elimination half-life can only be calculated once absorption and distribution are complete, which is difficult to determine following acute ingestion (hence the term ‘apparent’ elimination half-life) ( Roberts and Buckley, Arachidonate 15-lipoxygenase 2007a). Biphasic convex concentration–time curves are observed in other poisonings which are susceptible to non-linear kinetics ( Roberts and Buckley, 2007a). It is worthwhile determining physiological factors contributing to the biphasic convex plasma concentration–time profile because this may guide research into kinetic interventions for acute chlorophenoxy poisoning. Possible contributors include prolonged absorption, multi-compartmental concentration and pH-dependent distribution, saturable clearance or the influence of conjugated metabolites.
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