Metabolism and exretion of 3-hydroxyphenyltrimethylammonium and neostigmine.

Abstract

1. 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.2. A method is described for the separation and estimation of free and conjugated 3-OH PTMA in urine and liver.3. 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.4. 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.5. In the hen 3-OH PTMA is rapidly excreted by renal tubular secretion.6. 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.7. 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.