ERM Regulatory Services Ltd, Harrogate, United Kingdom of Great Britain and Northern Ireland.
ToxMetrics.com LLC, Midland, MICH, USA.
Xenobiotica. 2022 May;52(5):498-510. doi: 10.1080/00498254.2022.2100842. Epub 2022 Jul 28.
Metabolism data for MCPA in rat, dog and human shows a single oral dose is quantitatively and rapidly absorbed with evidence of non-linear kinetics at >100 mg/kg bw. The extent of metabolism is low and consistent between rat and human, with substantially higher metabolic conversion in dog. Parent accounts for 50%-67% dose in rat, ∼40% in human and 2%-27% in dog. No dog specific metabolite is apparent.In rat and human, MCPA and metabolites are rapidly eliminated in urine (65%-70% within 24 h) but in dog, excretion is urine and faeces (20%-30% within 24 h), with renal excretion saturating between 5 and 100 mg/kg bw.The species difference in excretion is reflected in pharmacokinetics. Terminal half-life is similar in rat and human (15-17 h) but higher in dog (47 h). Modelling shows species differences in single dose kinetics profoundly affect systemic exposure following repeat dosing.The difference in renal excretion and systemic exposure of MCPA between dogs and rats has been attributed to species differences in active transporters (OAT1/OAT3). A new flux study in renal proximal tubules supports this hypothesis with net secretion in rat and human of a similar magnitude but significantly less in dog.
在大鼠、犬和人体内，MCPA 的代谢数据表明，单剂量口服可被定量快速吸收，在 >100mg/kg bw 时存在非线性动力学的证据。代谢程度较低，在大鼠和人体内一致，犬体内的代谢转化率显著更高。母体在大鼠中的占比为 50%-67%，在人体内为 40%，在犬体内为 2%-27%。在犬体内没有明显的特定代谢物。在大鼠和人体内，MCPA 和代谢物迅速从尿液中排出（24 小时内 65%-70%），但在犬体内，排泄是尿液和粪便（24 小时内 20%-30%），肾排泄在 5-100mg/kg bw 之间达到饱和。排泄的种间差异反映在药代动力学中。大鼠和人体内的终末半衰期相似（15-17 小时），但犬体内更高（47 小时）。模型显示，单次剂量动力学中的种间差异对重复剂量后的系统暴露有深远影响。犬与大鼠之间 MCPA 的肾排泄和系统暴露差异归因于主动转运体（OAT1/OAT3）的种间差异。在肾近端小管中的一项新的流量研究支持了这一假设，大鼠和人体内的净分泌相似，但犬体内的净分泌显著减少。
