Distribution of neostigmine and its metabolites in rat tissues after acute and chronic administration

Abstract

The rate and pattern of neostigmine metabolism in different tissues of rat were studied after acute and chronic subcutaneous administration of the 14C-labelled drug. Radioactivity in plasma, liver, kidney and muscle was determined and the analysis of different metabolites and neostigmine was carried out by paper chromatography. The t 1 2 of parent drug and its metabolites is on the average 10 min in plasma, 33 min in liver, and 1.5 hr in muscle. Neostigmine is metabolised in the liver at a rate of 2.24 × 10 −2 μmol/min/g (wet weight) and 3-hydroxyphenyltri-methylammonium (3-HPTMA) is metabolized at a rate of 2.89 × 10 −2 μmol/min/g. Metabolic degradation of neostigmine proceeds in muscle at a rate of 2.1 × 10 −2 μmol/g. During chronic administration, the concentration of neostigmine and its metabolites rose in liver between day one to eight from 0.63 to 5.89 μmolg of tissue and in muscle from 0.085 to 0.39 μmol/g of tissue. Liver contained the highest concentration of glucuronide of 3-HPTMA (G-3-HPTMA) followed by neostigmine and 3-HPTMA. G-3-HPTMA concentration was 0.321 μmol on day 1 and increased to 2.89 μmol/g liver on day 8. The neostigmine concentration increased from 0.14 to 1.62 μmol/g of liver during the same period. Similar increases in the concentration of neostigmine and its metabolites were also obseved in muscle under the same conditions. 3-Hydroxyphenyldimethyl amine (3-HPDMA) and an unknown metabolite also consistently increased in liver and muscle.