Species differences in the intestinal excretion of emepronium.

A substantial proportion of a parenteral dose of emepronium given to dogs is excreted via the gastrointestinal tract by biliary excretion and by excretion through the intestinal mucosa (Hallén et al. 1979). In the present paper the different routes of elimination were further investigated in mouse and man and compared to the dog. The disposition of emepronium-derived radioactivity (14C) in the three species showed that about 45% was excreted via urine and 55% via faeces. The proportion of the faecal excretion of 14C that could be referred to the intestinal route differed between the species and was about 20% in man, 60% in the mouse and most pronounced, 80%, in the dog.

Gastrointestinal transit rate-related absorption of emepronium: a study in mice.

The gastrointestinal (GI) absorption in mice of the anticholinergic quaternary ammonium compound emepronium, assessed by the urinary excretion of radioactivity and unchanged drug, increased from 1% to 7% and from 0.5% to 5%, respectively, in the dose range 0.1 to 40 mg/kg, whereafter a plateau was reached. Changes in the metabolism were evident at doses exceeding 80 mg/kg when 80% of the radioactivity was excreted as unchanged emepronium, as compared to 50% at lower doses. No dose-dependent urinary excretion of radioactivity was detected following intravenous injection. The increase in the fraction of the dose excreted in the urine after oral administration therefore cannot be easily explained by a dose-dependent metabolism or renal excretion. However, a relationship was seen between the reduced gastrointestinal motility, produced by increasing doses of the drug, and the increased bioavailability. Atropine sulphate given subcutaneously (1-50 mg/kg) more than doubled the urinary recovery of a small pharmacologically inactive oral dose of emepronium (5 mg/kg) and thus confirmed the transit rate-dependent absorption of emepronium. The superimposed effect of the pharmacological action on the GI transit rate, derived from the inherent property of an anticholinergic drug, may be of special significance for a drug with a low degree of absorption and a high variability, such as has been observed in clinical trials with the quaternary drug emepronium (Cetiprin).

Ion pair formation and gastrointestinal absorption of emepronium.

Ion pair forming agents were evaluated in vitro for their ability to form lipophilic ion pairs with the quaternary ammonium compound emepronium and in vivo to enhance its gastrointestinal absorption. A 5- to 100-fold excess of trichloroacetate (TCA), diethylhexylphosphate (DEHPA), heptafluorobutyrate (HFBA), sodium lauryl sulphate (SLS), bromide or chloride all increased the extractability of the emepronium ion into methylene chloride. The additive with the most marked effect on the apparent partition coefficient of emepronium (Kapp) was SLS. At emepronium 10(-4) M, Kapp increased from a basal value of 0.1 to 368 with a 100-fold molar excess. However, the increased partitioning to methylene chloride was not reflected in an increased gastrointestinal absorption of the emepronium ion when this was given orally to mice. When intestinal juice, instead of distilled water or buffer, was used as the aqueous phase, the partition coefficient was markedly higher (Kapp approximately 2) but it was significantly less influenced by addition of sodium lauryl sulphate (Kapp approximately 6). The preexisting positive influence of the intestinal juice on the lipophilic character of emepronium and the rather limited additive effect of agents that form lipophilic complexes with emepronium, lead to the conclusion that the ion pair concept is not a suitable approach to enhance the gastrointestinal absorption of this drug.

Pharmacokinetics and pharmacodynamics of emepronium bromide (Cetiprin) after intravenous administration in man.

Intravenous doses of 1, 5, 10 and 15 mg of emepronium bromide were given to three healthy volunteers. Emepronium serum concentration declined in a triexponential manner with half-lives between 2.2-3.0 min., 1.0-1.6 hours and 5.1-13 hours, respectively. The initial dilution space (volume of the central compartment) varied between 4.1-7.5 l. The area under the serum concentration time curve increased linearly with dose, indicating constancy of total serum clearance (range: 24-38 l/hr) with dose. The renal clearance of emepronium varied with serum concentration; secretion in addition to glomerular filtration was evident. Tubular secretion of emepronium was half-saturated at serum concentrations of approximately 50 nmol/l. No obvious drug-related effect on blood pressure was noted, whereas salivary secretion decreased and heart rate increased with 10-15% at emepronium serum concentrations of about 200 nmol/l. ECG recordings were without abnormalities after slow intravenous injections of emepronium bromide in doses of up to 15 mg. Since no adverse effects were noted, intravenous administration of emepronium bromide may be an alternative in situations where the drug is now used intramuscularly e.g. severe tenesmus in the urinary bladder.

[Elimination of organic cations from the eye]. / Elimination organischer Kationen aus dem Auge.

Substances injected into the vitreous cavity leave the eye partly by diffusion into the flowing aqueous, but sometimes also by other mechanisms. To look for such other mechanisms removing organic cations from the rabbit eye, 5 labeled quaternary ammonium compounds were injected intravitreally, mixed with labeled sucrose. The latter leaves essentially by way of the aqueous only. After predetermined times had elapsed the rabbits were killed, and the radioactivity remaining in each eye was measured after combustion of the dried eye bulb. The anticholinergic drug Emepronium disappeared faster than sucrose but only after a delay of many hours. The main experiments were therefore concerned with the time interval 24-48 h after injection. The N- hexylhomologue of Emepronium ' Cetihex ' and the non-sedative antihistamine Aprobit were not eliminated faster than sucrose during this time interval. Since the molecular weights of these quaternaries are similar to that of sucrose and their free diffusion rate should be similar, the present experiments over a limited time interval have proved the existence of an elimination mechanism (besides aqueous flow) only for Emepronium. Tetramethylammonium and tetraethylammonium disappeared markedly faster than sucrose. Since there is no satisfactory way to take their much lower molecular weight into account, the question of a special system for these cations remains open.

Organic anion and cation transport in vitro by dog choroid plexus: effects of neuroleptics and tricyclic antidepressants.

Dog lateral choroid plexus accumulates the cation 14C-emepronium and the divalent anion 125I-iodipamide in vitro. At 10 micron, high potency neuroleptics with a substituted piperazine side chain and also haloperidol depress only the uptake of the cation and even stimulate the uptake of the anion. In contrast, at 1--10 micron, the accumulation of both test substances is inhibited by neuroleptics and tricyclic antidepressants with an aliphatic side chain. Such unspecific effects on seemingly unrelated transport systems at concentrations reached clinically in the CSF might explain some side actions of low potency neuroleptics and antidepressants.

Organic cation uptake in vitro by the rabbit iris-ciliary body, renal cortex, and choroid plexus.

The uptake in vitro of radioactively labeled test substances was studied in tissues from albino rabbits. Choroid plexus, slices of outer renal cortex, and iris-ciliary body were incubated in a K-rich medium containing one of the cations 14C-Emepronium (Cetiprin), 14C-tetraethylammonium, 14C-choline, or 125I-o-iodobenzyltrimethylammonium and sometimes the anions 131I-o-iodohippurate and 125I-iodipamide. Choroid plexus and renal cortex accumulated all test substances, some to very high tissue-medium ratios. The iris-ciliary body preparation accumulated the anions well but the organic cations only weakly. The only convincing uptake was that of Emepronium. The affinity of this uptake system seemed to be similar to that in the kidney, half-saturating around 10(-4)M Emepronium.