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

Abstract

The elimination kinetics of [14C]‐neostigmine iodide and [14C]‐3‐hydroxyphenyltrimethylammonium iodide (3‐OH PTMA) have been studied in the rat. The presence of a renal secretory pathway for neostigmine and 3‐OH PTMA has been confirmed. 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. 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. 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.

THE PHARMACOKINETICS OF PYRIDOSTIGMINE AND 3‐HYDROXY‐N‐METHYLPYRIDINIUM IN THE RAT: DOSE‐DEPENDENT EFFECTS AFTER PORTAL VEIN ADMINISTRATION

“…These results are similar to those reported for the related quaternary amines neostigmine and its metabolite 3-OH PTMA (Barber & Bourne, 1974). It is also possible that the lower fraction of the metabolite excreted after jugular venous administration may be indicative of competition for a renal secretory site by the initial high concentration of pyridostigmine attained by this route of administration.…”

“…The fraction of the dose eliminated as pyridostigmine was reduced and the metabolite fraction greatly increased after portal vein administration of a given dose when compared to jugular vein administration of the same dose (Table 1); thus pyridostigmine is subject to metabolism during the first passage through the liver. These results are similar to those reported for the related quaternary amines neostigmine and its metabolite 3-OH PTMA (Barber & Bourne, 1974). It is also possible that the lower fraction of the metabolite excreted after jugular venous administration may be indicative of competition for a renal secretory site by the initial high concentration of pyridostigmine attained by this route of administration.…”

“…Pharmacokinetic studies with other quaternary amines (Barber & Bourne, 1974) have not established unequivocally whether these compounds are eliminated from the region in which they are first distributed. On the one hand, both neostigmine and 3-hydroxy-phenyltrimethylammonium (3-OH PTMA) are subject to a first pass effect.…”

“…Recent evidence suggests that many drugs may be eliminated in this manner (Wagner, 1973). Pharmacokinetic studies of the quaternary amines neostigmine and 3-hydroxyphenyltrimethylammonium have demonstrated that both these compounds are eliminated by dose-dependent processes and subject to 'first pass' metabolic effects by the liver (Barber & Bourne, 1974).…”

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

“…3-OH PTMA This compound was separated from its metabolite by the liquid cation exchange procedure without the addition of NaOH (Barber & Bourne, 1974).…”