Metabolism and excretion of 3‐hydroxyphenyltrimethylammonium and neostigmine

Abstract

Carbon‐14 labelled 3‐hydroxyphenyltrimethylammonium (3‐OH PTMA), an active metabolite of neostigmine, has been given to rats by intramuscular injection and its excretion, distribution and metabolism have been studied. A method is described for the separation and estimation of free and conjugated 3‐OH PTMA in urine and liver. In the first hour, about 20% of a dose is excreted in the urine as free 3‐OH PTMA and thereafter the rate of excretion of glucuronide conjugate exceeds that of free 3‐OH PTMA. In 24 hr 76.8% of the dose is excreted in urine mainly as the conjugate. The peak concentration of radioactivity in blood occurs within 30 min and in liver within 1 hr after administration. More than 90% of the radioactivity in liver occurs as the glucuronide conjugate. Relatively high concentrations of radioactivity were found in liver and heart. In the hen 3‐OH PTMA is rapidly excreted by renal tubular secretion. Experiments with carbon‐14 labelled neostigmine show that up to 1 hr mainly unchanged neostigmine is excreted in urine; thereafter increasing amounts of free 3‐OH PTMA and its glucuronide conjugate are excreted. It is concluded that the duration of action of neostigmine is determined by its rapid renal excretion and by its metabolism to the glucuronide conjugate of 3‐OH PTMA.

The Pharmacokinetics of Neostigmine and 3‐hydroxyphenyltrimethylammonium in the Rat: Dose‐dependent Effects After Portal Vein Administration

“…The clearance ratio was always greater than 1, confirming the previous report (Husain et al, 1969) Table 4. The clearancratio was not statistically significantly different from 1 at plasma levels of 0.056-0.255 ,molar glucuronide; however between plasma levels of 0.344-0.625 mmolar, the clearance ratio was significantly less than 1 (see Table 4 Figure 1.…”

“…Comparison of the clearance of neostigmine and 3-OH PTMA with that of inulin confirmed that both compounds are eliminated by renal tubular secretion as previously described (Roberts et al, 1965a;Husain et al, 1969 (Gibaldi & Feldman, 1972).…”

“…This procedure extracts only 3-OH PTMA as shown by the following: samples of urine containing [14CJ -3-OH PTMA iodide and its metabolites were subjected to paper electrophoresis in barbitone buffer, pH 6.9, as previously described (Husain et al, 1969 Table 1 confirm that 3-OH PTMA only is extracted by NaTPB. The amount of metabolites present was determined by difference between total 14C and parent drug extracted.…”

“…The principal metabolite has been identified as 3-hydroxyphenyltrimethylammonium iodide (3-OH PTMA) which is further metabolized to a glucuronide and several minor metabolites (Husain, Roberts, Thomas & Wilson, 1969;Somani, Roberts, Thomas & Wilson, 1970). Biliary excretion has been shown to be a minor route of elimination of neostigmine and its metabolites (Calvey, 1966;Somani, Wright & Calvey, 1970).…”

The Relationship Between the Pharmacokinetics, Cholinesterase Inhibition and Facilitation of Twitch Tension of the Quaternary Ammonium Anticholinesterase Drugs, Neostigmine, Pyridostigmine, Edrophonium and 3‐hydroxyphenyltrimethylammonium

“…Previous pharmacokinetic studies on neostigmine, pyridostigmine and edrophonium have shown that the principle metabolite of neostigmine is 3-hydroxyphenyltrimethylammonium (3-OH PTMA) which is further metabolized to a glucuronide conjugate (Hussain, Roberts, Thomas & Wilson, 1969). It has been reported that 3-OH PTMA has a facilitatory action at the neuromuscular junction .…”