The pharmacokinetics of neostigmine and 3-hydroxyphenyltrimethyl- ammonium in the rat: dose-dependent effects after portal vein administration.

1 The elimination kinetics of [(14)C]-neostigmine iodide and [(14)C]-3-hydroxyphenyltrimethyl-ammonium iodide (3-OH PTMA) have been studied in the rat.2 The presence of a renal secretory pathway for neostigmine and 3-OH PTMA has been confirmed.3 For neostigmine and 3-OH PTMA, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that both compounds are subject to extensive metabolism during the first passage through the liver.4 Neostigmine was eliminated by dose-independent kinetics after jugular vein administration but dose-dependent after portal vein administration. In the latter case the fraction eliminated as neostigmine increased with increasing dose. This increase was not accompanied by any change in the fraction of the metabolites eliminated.5 After portal vein administration of 3-OH PTMA, the fraction of the dose eliminated as 3-OH PTMA also increased with increasing dose. This change was accompanied by a decrease in the fraction of the metabolites eliminated which were excreted at a constant rate.