piperidines and fenoctimine

The effect of fenoctimine, a new anti-secretory agent, has been studied on food stimulated acid secretion in six normal volunteers. When tested between 2 and 4 h after dosing, and compared with placebo, fenoctimine 50 mg inhibited acid secretion by a mean of 29%, 150 mg by 43% and 250 mg by 47%.

Topics: Adult; Bicarbonates; Food; Gastric Acid; Humans; Hydrogen-Ion Concentration; Male; Piperidines

1. The metabolism of fenoctimine (Fn) was studied in rat, dog and man following administration of 14C-Fn sulphate. 2. Seventeen Fn metabolites were isolated by hplc and tlc from rat bile, dog bile, dog urine, human urine, human faecal extracts, and human plasma and identified using nmr and MS. 3. The identified metabolites accounted for 75% of total radioactivity in rat bile, 80% in dog bile, and 40% in dog urine samples. In man, 90% of the urinary, 70% of the faecal, and > 50% of the plasma total radioactivity were identified. 4. Three major pathways for Fn metabolism were proposed. These pathways involved imino-bond cleavage, aromatic hydroxylation and oxidation of the aliphatic chain. 5. The imino-bond cleavage pathway was dominant in all species. However, the other two pathways differed in quantitative importance among the species studied. 6. The aromatic hydroxylation pathway appeared to be the most important means of biotransformation of Fn in dog since all but two of the metabolites were formed by this route. 7. The aliphatic oxidation pathway appeared to be important to the biotransformation of Fn in man and produced three major metabolites.

Topics: Animals; Anti-Ulcer Agents; Bile; Biotransformation; Chromatography, High Pressure Liquid; Dogs; Humans; Male; Piperidines; Rats

Fenoctimine sulphate (4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine sulphate) and one of its metabolites, 1-formyl-4-(diphenylmethyl) piperidine (RWJ-34321), were incubated with a rat liver post-mitochondrial supernatant preparation and an NADPH generating system. The metabolites, 7-hydroxyoctyl fenoctimine and 7-oxoocytl fenoctimine were identified as in vitro oxidative metabolites of fenoctimine on the basis of mass spectrometry and thin layer chromatography in comparison to authentic samples. RWJ-34321, a third metabolite, was confirmed as a hydrolyzed product of fenoctimine on the same basis. In separate incubations with RWJ-34321, one metabolite (4-(diphenylmethyl)piperidine), was identified as an in vitro metabolite of RWJ-34321 by mass spectrometry and thin layer chromatography. Thus, the in vitro metabolism of fenoctimine by rat liver homogenates resulted in the oxidation of the aliphatic chain at the seven carbon, initially to an alcohol and then to a ketone. The metabolism of RWJ-34321 resulted in decarbonylation of the formyl carbon.

Topics: Animals; Anti-Ulcer Agents; Chromatography, Thin Layer; In Vitro Techniques; Male; Mass Spectrometry; Mitochondria, Liver; Piperidines; Rats; Rats, Wistar

The properties of K+-stimulated ATP hydrolysis (K+-ATPase) and vesicular accumulation of H+ (H+ accumulation) in hog gastric microsomes were investigated. The microsomes consisted of smooth surfaced vesicular particles, 70-300 nm in diameter. Both the activities of ATPase and the vesicular accumulation of H+ were stimulated by K+ in the presence of Mg2+, and enhanced by the K+-ionophore, valinomycin. However, there were differences in regulation of K+-ATPase and H+ accumulation by K+ ions, i.e. K+ at concentrations higher than 10 mM decreased K+-ATPase activity but further enhanced H+ transport. This observation suggests that the two reactions are partly independent. The H+ accumulation was inhibited by omeprazole, fenoctimine, spermine, and NaSCN, but not by cimetidine, prostaglandin E2, and atropine. The inhibitory effect of omeprazole on H+ accumulation paralleled the inhibition of K+-ATPase, while fenoctimine, spermine, and NaSCN suppressed H+ accumulation, without inhibiting K+-ATPase, under appropriate concentrations. In addition, the spontaneous diffusion of H+ across the microsomal membrane was markedly enhanced by fenoctimine, but not by the other agents used. These results indicate that omeprazole inhibits H+ accumulation by inhibiting K+-ATPase, fenoctimine suppresses H+ accumulation mainly by increasing the loss of accumulated H+ from the microsomal vesicles, spermine and NaSCN reduce H+ accumulation by inhibiting the transport of H+ into microsomal vesicles.

Topics: Adenosine Triphosphatases; Animals; Diffusion; Gastric Mucosa; H(+)-K(+)-Exchanging ATPase; Magnesium; Microscopy, Electron; Microsomes; Piperidines; Potassium; Sodium Cyanide; Spermine; Swine; Valinomycin

Fenoctimine (1a), a nonanticholinergic inhibitor of gastric acid secretion in dogs and rats, was evaluated as a gastric antisecretory agent in humans. In humans it exhibited weak antisecretory activity and caused anticholinergic-like side effects such as dry mouth and nasal passages. Studies of the metabolic fate of fenoctimine in humans, dogs, and rats provided structures of the resultant metabolites. These were synthesized and tested for antisecretory and anticholinergic activity. The human metabolites were all less active than fenoctimine as antisecretory agents, and some displayed significant anticholinergic activity. These results suggest that the unexpectedly weak effect of fenoctimine as a gastric antisecretory agent in humans, as well as anticholinergic effects, may be due to its extensive metabolism, which is different from that seen in dog and rat.

Topics: Animals; Chemical Phenomena; Chemistry; Dogs; Female; Gastric Acid; Gastric Mucosa; Guinea Pigs; Humans; Ileum; Parasympatholytics; Piperidines; Rats; Receptors, Cholinergic

Topics: Anti-Ulcer Agents; Chromatography, Gas; Drug Stability; Humans; Indicators and Reagents; Nitrogen; Phosphorus; Piperidines

An in situ rat intestinal preparation was modified to include portal and jugular venous blood collection techniques as well as sampling from the intestinal lumen. Viability could be maintained for 3 h. The utility of the preparation was examined by studying the disposition of four model drugs, each with differing characteristics with respect to absorption and presystemic metabolism. Haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1- butanone), a reference compound used for model development, disappeared from the intestinal lumen with a half-life of 14 +/- 3 min. When the antiarthritic agent, tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate), was studied in the preparation, it was rapidly absorbed (t1/2 for disappearance from the intestinal lumen = 8 min), achieved plasma concentrations comparable to in vivo data, and underwent little presystemic elimination. In contrast, fenoctimine sulfate (4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine sulfate), an antisecretory compound, disappeared more slowly from the intestinal lumen (t1/2 = 60 min), was present in portal plasma, but was not detected in systemic plasma. Extensive hepatic first-pass elimination of fenoctimine was evident. Tolmetin glycine amide (N-([1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetyl)glycine), a tolmetin prodrug, disappeared from the intestinal lumen very slowly (t1/2 approximately 3 h) compared with the other agents tested. It was determined that this drug was being hydrolyzed presystemically to tolmetin by the intestinal mucosa and the liver. These results establish the utility of this intestinal preparation for studying drug absorption and presystemic elimination.

Topics: Animals; Electrolytes; Enzymes; Haloperidol; Intestinal Absorption; Jugular Veins; Male; Pharmaceutical Preparations; Piperidines; Portal Vein; Rats; Rats, Inbred Strains; Tolmetin

The effects of fenoctimine, an inhibitor of gastric acid secretion, on the microsomal (H+ + K+)-ATPase were studied. In the micromolar concentration range, fenoctimine inhibited hydrolysis of ATP and p-nitrophenyl phosphate by the (H+ + K+)-ATPase. Inhibition was reversible and noncompetitive with substrate. The apparent Ki was dependent on the concentration of membranes, being increased by added liposomes or high microsomal membrane concentrations. Over the concentration range that (H+ + K+)-ATPase was inhibited, fenoctimine increased the turbidity of microsomal suspensions. The effects of fenoctimine were not specific for the gastric (H+ + K+)-ATPase, since the hydrolytic activities of the (Na+ + K+)-ATPase and mitochondrial ATPase were also inhibited by the drug. These results suggest that inhibition of hydrolysis may not be the direct result of an interaction between the (H+ + K+)-ATPase and fenoctimine but the secondary effect of a fenoctimine-induced perturbation of the microsomal membrane.

Topics: Adenosine Triphosphatases; Animals; Anti-Ulcer Agents; Dose-Response Relationship, Drug; Gastric Acid; Gastric Mucosa; H(+)-K(+)-Exchanging ATPase; In Vitro Techniques; Piperidines; Sodium-Potassium-Exchanging ATPase; Swine

Large differences in induced cellular toxicity were observed in the presence or absence of a rat liver microsomal metabolizing system (S-9) during drug testing in the mouse lymphoma assay. After studying the fate of three drugs in this test system, several mechanisms were demonstrated whereby S-9 reduced cellular toxicity. For N-(4-hydroxyphenyl)retinamide (HPR), fenoctimine sulfate and methyl palmoxirate, the drug concentrations (EC50) in the presence of S-9 were, respectively, 11.5, 14.3 and 4.1 times the concentrations required to achieve comparable levels of toxicity in the absence of S-9. HPR was metabolized by the S-9 and sequestered in the microsomal membranes. This was associated with a marked reduction in the cellular accumulation of the drug. The reduced toxicity of fenoctimine sulfate in the presence of S-9 was associated with extensive biotransformation to polar metabolites. This was accompanied by a reduction of radioactivity associated with the cells from 5.7% to 0.4% of the administered drug. Methyl palmoxirate was rapidly converted to its acid, palmoxirate, by horse serum enzymes present in the treatment medium. This provides an example of metabolism by a test system component other than the S-9 or lymphoma cells. The reduced toxicity of this drug in the presence of S-9 was attributed to further metabolism of palmoxirate and a reduction of the proportion of total radioactivity associated with the cells from 3.1% to 0.4%. These results emphasize the need for pilot toxicity studies, especially when components of the test system are varied, to assess the effect of drug concentration on the toxic response.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biotransformation; Cell Division; Cell Line; Cells, Cultured; Epoxy Compounds; Ethers, Cyclic; Fenretinide; Leukemia L5178; Leukemia, Experimental; Male; Mice; Microsomes, Liver; Mutagenicity Tests; Mutagens; Piperidines; Propionates; Rats; Tretinoin

Fenoctimine (4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine) sulfate was evaluated for gastric antisecretory activity in the acute gastric fistula rat and chronic gastric fistula dog. It showed potent gastric antisecretory activity of long duration in the rat, and was more potent on a mg/kg basis than cimetidine. In the dog, fenoctimine showed significant activity against gastrin tetrapeptide, histamine, and bethanechol. It was least potent against bethanechol, indicating a lack of significant anticholinergic activity in the dog at the doses tested. It had a long duration of action in the dog with doses of 6 mg/kg, showing significant activity even at 24 hr. Fenoctimine does not appear to fit the spectrum of activity associated with other known antisecretory agents and may have a unique mechanism of action related to effects directly on parietal cells.

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Cimetidine; Dogs; Drug Evaluation, Preclinical; Drug Tolerance; Female; Gastric Fistula; Gastric Mucosa; Injections, Intraperitoneal; Piperidines; Rats; Rats, Inbred Strains

4-(Diphenylmethyl)-1-piperidinemethanimine (1) is a potent oral gastric antisecretory agent in rats but contains a strong anticholinergic component. Since a nonanticholinergic gastric antisecretory drug would be useful in the treatment of peptic ulcer disease, a program was initiated by us to find such an agent based on 1. Compound 1 contains structural elements common to the anticholinergics atropine and homatropine. Studies on the structure-activity relationships of these compounds and their derivatives have revealed certain modifications that diminish or abolish anticholinergic activity. The application of these modifications to the design of analogues of 1 afforded an antisecretory compound, 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine (3h, fenoctimine), which exhibited no anticholinergic activity. Fenoctimine is undergoing clinical trial as a gastric antisecretory drug.

Topics: Animals; Anti-Ulcer Agents; Binding, Competitive; Carbachol; Female; Gastric Acid; Gastric Emptying; Piperidines; Quinuclidinyl Benzilate; Rats; Receptors, Muscarinic; Structure-Activity Relationship