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At least 19 recordsLinked to original sources

PubMed1985

Comparison of pulmonary accumulation of pyrilamine and pyrilamine N-oxide.

Our previous studies have indicated that a phenothiazine drug, chlorpromazine, and a tricyclic antidepressant, imipramine, are metabolized by the isolated perfused rat lungs via N-oxidation from whence their N-oxides are released into the circulation. This work was undertaken to compare the pulmonary accumulation of another pneumophilic tertiary amine drug, pyrilamine, with that of its N-oxide. Approximately 10-fold greater accumulation of pyrilamine than that of its N-oxide was observed in the mouse lung after a single pass perfusion with 40 microM of the drug for a 3 min period. The largest difference between accumulation of pyrilamine and its N-oxide was noted in the lung among the various tissue slices tested, suggesting the tissue specificity of affinity.

Aminopyridines↗

PubMedDate not supplied

Microbial transformation of the antihistamine pyrilamine maleate. Formation of potential mammalian metabolites.

Fourteen fungi were found to metabolize pyrilamine (2-[(2-dimethylaminoethyl)(p-methoxybenzyl)amino]pyridine). Two Cunninghamella elegans strains transformed essentially all of the pyrilamine added after 144 hr. After 48 hr of incubation, C. elegans ATCC 9245 metabolized 76% of the antihistamine into methylene chloride-extractable pyrilamine metabolites. These organic-soluble metabolites were isolated by HPLC and the major metabolites were characterized by comparison of their chromatographic, mass, and 1H-NMR spectral properties with those of authentic compounds. The major metabolite was identified as 2-[(2-dimethyloxyaminoethyl)(p-methoxybenzyl)amino]pyridine (N-oxide derivative of pyrilamine). Other metabolites identified were 2-[(2-dimethylaminoethyl)(p-hydroxybenzyl)amino]pyridine, 2-[(2-methylaminoethyl)(p-methoxybenzyl)amino]pyridine, and 2-[(2-methylaminoethyl)(p-hydroxybenzyl)amino]pyridine. These metabolites represent O-demethylated, N-demethylated, and O- and N-demethylated derivatives of pyrilamine, respectively. The mutagenic activities of the N-oxide and the N- and O-dealkylated pyrilamine derivatives, and pyrilamine maleate were measured by reversion of Salmonella typhimurium strains TA97, TA98, TA100, and TA102. Pyrilamine maleate and the three microbial metabolites showed no appreciable mutagenic activity in any of the S. typhimurium tester strains. The metabolism of pyrilamine by 12 other filamentous fungi and yeast strains was much less when compared to C. elegans and ranged from 3.8% to 12.2%. The fungal metabolism of pyrilamine may be useful in predicting results of mammalian metabolism and in readily providing sufficient quantities of metabolites for further toxicological studies.

Aminopyridines↗

PubMedDate not supplied

The metabolism and elimination of pyrilamine maleate in the rat.

The metabolism and elimination of pyrilamine (2-[(2-dimethylamino-ethyl)(p-methoxybenzyl)amino]pyridine) were characterized after the iv administration of 7.0 mg/kg or 0.7 mg/kg pyrilamine maleate plus [14C]pyrilamine maleate to adult male Fischer-344 rats. Approximately 29% and 38% of the administered dose was excreted in the urine in the first 24 hr in the high and low dose groups, respectively, as determined by liquid scintillation spectrometry. Fecal excretion accounted for 27% and 30% of the administered dose in the first 24 hr in the high and low dose groups, respectively, as confirmed via combustion analysis. The 24-hr urinary metabolic products consisted of one major and four minor radiolabeled compounds. The major metabolite was isolated by reversed-phase high performance liquid chromatography and identified as the O-glucuronic acid conjugate of O-demethyl pyrilamine. This was accomplished by comparison of the chromatographic characteristics of this metabolite's aglycon with that of an authentic standard of O-demethyl pyrilamine and fast atom bombardment mass spectrometry of the unhydrolyzed conjugate. Pyrilamine and its N-oxide and O-demethyl derivatives were also identified after isolation by reversed-phase high performance liquid chromatography and comparison of their mass spectral and/or chromatographic properties with those of authentic compounds. The plasma metabolic profile was essentially the same as the urinary profile except for the absence of O-demethyl pyrilamine. The plasma elimination of pyrilamine fit a one-compartment open model and was first order. The terminal plasma elimination half-life of pyrilamine did not increase with increasing doses (2.3 hr, 0.7 mg/kg; 1.5 hr, 7.0 mg/kg) and thus pyrilamine does not exhibit dose-dependent elimination.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopyridines↗

PubMed1990

High-performance liquid chromatography of the antihistamine pyrilamine and its N-oxide using electrochemical detection.

The electrochemical behavior of the over-the-counter antihistamine drug pyrilamine and its N-oxide analogue, have been studied by several voltammetric methods. Cyclic voltammograms of pyrilamine maleate in 0.1 M ammonium acetate at pH 7.0 indicated a quasi-reversible electrode process by observing a wave at + 0.85 V and + 1.30 V in the initial anodic sweep followed by a wave at - 1.30 V versus Ag/AgCl. Differential pulse and hydrodynamic voltammetry of pyrilamine and the N-oxide were examined to determine oxidation potentials for use in high-performance liquid chromatography with electrochemical detection (HPLC-ED). Differentiation between pyrilamine and its N-oxide was achieved in HPLC-ED analyses at a detection potential of + 0.7 V and + 0.9 V versus Ag/AgCl with tandem ultraviolet detection at 254 nm. Utility of the HPLC-ED method was demonstrated by the analysis of pyrilamine and the N-oxide in microbial biotransformation samples.

Biotransformation↗

PubMedDate not supplied

Metabolism of pyrilamine maleate in Fischer 344 rats, Part I: Activity excretion profiles.

Male and female Fisher 344 rats (12 per group) were dosed by gavage with either 2 or 10 mg (based on the free amine) pyrilamine maleate containing about 12 and 6 muCi 14C-pyrilamine maleate, respectively, to determine excretion of the activity as a function of dose and sex with time. Urine and feces were collected at timed intervals through 144 h. Most of the dose (about 70%) was eliminated within 48 h through the urine and feces, but only about 80% of the total dose was recovered during the experiment. Less than 1% of the total dose remained in the rats at the end of the test period. In an additional experiment to determine the location of the remainder of the dose (about 20%), male rats were dosed with 2 mg pyrilamine maleate containing 14C-pyrilamine maleate. After 144 h, exhaustive washing of the cages resulted in recovery of approximately 20% of the dose, thus identifying its location. There were no significant sex or dose related differences observed in the total amount of 14C that was eliminated through the urine or feces and recovered. Urine and feces are the major routes of elimination of pyrilamine maleate in the Fischer 344 rat. The urinary route of elimination was more predominant than the fecal route in both sexes at either dose.

Aminopyridines↗

PubMed1989

Solubilization and characterization of the pyrilamine-binding protein from cultured smooth muscle cells.

The cultured smooth muscle cell line DDT1MF-2 expresses a large number (9.7 x 10(6) receptors/cell) of functional histamine H1-type receptors [J. Cell. Physiol. 134:367-375 1988]. Two different binding assays, gel filtration and polyethylene glycol precipitation, indicated that the [3H]pyrilamine binding activity was solubilized by 1% digitonin with binding characteristics similar to those of intact cells. The solubilized proteins were then purified by sequential gel filtration, chromatofocusing, and reverse phase high pressure liquid chromatography. The calculated molecular weight of this purified pyrilamine-binding protein was 38-40 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. [3H]Pyrilamine binding to these 38-40-kDa proteins indicated a single class of binding site with a Kd of 288 nM, which is equivalent to that of intact cells and digitonin-solubilized proteins. The computer analysis Scatfit also indicated that one molecule of [3H]pyrilamine bound to one molecule of purified protein. Furthermore, a polyclonal antibody raised against the purified protein recognized the 38-40-kDa band by Western blotting techniques, specifically bound to the cell surface of DDT1MF-2 cells, and inhibited [3H]pyrilamine binding to these cells in a dose-dependent manner. These data strongly suggest that the purified 38-40-kDa protein is part of an antagonist binding domain on the histamine H1 receptor on DDT1MF-2 cells.

Aminopyridines↗

PubMed1983

The general toxicology unknown. II. A case report: doxylamine and pyrilamine intoxication.

A general toxicology unknown case is presented to demonstrate our systematic approach. A 20-year-old male was found dead with multiple suicide notes. Overdose was suspected but substances were not known. Blood alcohol was negative. Urine was analyzed by enzyme-multiplied immunoassay technique and was negative for all drugs assayed. Urine was then extracted with ethyl acetate:hexane (1:1) at pH 10 and back-extracted into 1.0N sulfuric acid. The acidic layer was adjusted to pH 10, and re-extracted with ethyl acetate:hexane (1:1). The residue was analyzed by gas chromatography (GC) on a 3% OV-101 column. It was found to be negative for all commonly screened substances. However, several unknown peaks were observed. Electron impact mass spectra of these unknown peaks were obtained and searched for in our computer library of more than 25000 mass spectra. These unknown peaks were identified as doxylamine and pyrilamine by gas chromatography/mass spectrometry. The base peak and molecular ion for pyrilamine were at m/z 121 and 285, respectively. The base peak for doxylamine was at m/z 58. No molecular ion was observed for doxylamine. Both doxylamine and pyrilamine are antihistamines, but are promoted and used in the management of insomnia. Quantitation was performed on a GC using dexbrompheniramine as an internal standard. Blood concentrations for doxylamine and pyrilamine were 0.7 and 7.0 mg/L, respectively. Concentrations in other tissues were determined. Death was caused by combined doxylamine and pyrilamine intoxication; the manner of death was suicide.

Adult↗

PubMed1988

Characterization of doxylamine and pyrilamine metabolites via thermospray/mass spectrometry and tandem mass spectrometry.

Analysis of doxylamine N-oxide and pyrilamine N-oxide as synthetic standards and biologically derived metabolites by thermospray mass spectrometry (TSP/MS) provided [M + H]+ ions for each metabolite. TSP/tandem mass spectrometry (TSP/MS/MS) of the [M + H]+ ions provided fragment ions characteristic of these metabolites. In addition, TSP mass spectrometry and TSP/MS/MS analysis of ring-hydroxylated N-desmethyldoxylamine, N-desmethylpyrilamine and O-dealkylated pyrilamine is also reported. A fragmentation pathway for analysis by MS/MS of pyrilamine and its metabolites is also proposed. The results demonstrate the utility of TSP/MS for biologically derived metabolites of pyrilamine and doxylamine.

Aminopyridines↗

PubMed1990

Analysis of rat urine for metabolites of pyrilamine via high-performance liquid chromatography/thermospray mass spectrometry and tandem mass spectrometry.

Combined high-performance liquid chromatography/thermospray mass spectrometry (HPLC/TSMS) and HPLC/thermospray tandem mass spectrometry (HPLC/TSMS/MS) were utilized for the analysis of rat urine for metabolites of pyrilamine. The sample was analyzed via HPLC/TSMS/MS in the parent ion mode in order to identify potential metabolites of pyrilamine. Then HPLC/TSMS/MS analysis in the daughter ion mode was performed to provide additional analytical selectivity plus enhanced fragmentation of suspected protonated molecules. By this methodology, suspected pyrilamine metabolites were confirmed to be in the sample and several novel metabolites of pyrilamine were discovered and tentatively identified.

Aminopyridines↗

PubMed1993

Noncompartmental and compartmental modeling of the kinetics of carbon-11 labeled pyrilamine in the human brain.

The kinetic pattern of a 11C-labeled histamine H1 receptor antagonist, [11C]pyrilamine, was investigated in the human brain by factor analysis of dynamic PET studies. Tissue time activity curves were also processed by compartment model curve fitting preceded by deconvolution analysis. Factor analysis revealed two statistically significant and physiologically meaningful kinetic patterns: one for specific and another for nonspecific binding of the radioligand. From these two factors a compartment model containing two tissue compartments (one for specific binding and another for nonspecific binding and free ligand) was constructed. The two-compartment model was also supported by the impulse response function, which was obtained by deconvolution and showed two components. The factor image constructed from factor two demonstrated a distribution pattern characteristic for brain regions rich (frontal, parietal, and temporal lobes) or poor (occipital lobe and cerebellum) in H1 receptors. Blockade of H1 receptors with unlabeled pyrilamine, diphenhydramine, or hydroxyzine caused a significant reduction of this factor. Blockade produced no significant changes in factor one representing nonspecific binding. We conclude that the kinetics of [11C]pyrilamine in the brain can be described by two tissue compartments, one related to the distribution of the H1 receptors. Factor analysis of dynamic studies can be used to locally separate these two compartments, for identification of regions rich and poor in H1 receptors and for noninvasive quantitative investigation of the effects of H1 receptor blockers such as pyrilamine, diphenhydramine, or hydroxyzine.

Adult↗

PubMed1995

Chronic feeding study of pyrilamine in Fischer 344 rats.

The antihistamine, pyrilamine maleate, was fed for up to 2 years to groups of 57 Fischer 344 (F344) rats of each sex at dietary levels of 0, 300, 1500, or 3000 ppm (free base). Eight or nine of these rats per sex and dose group were killed at 65 weeks to analyze hematology and clinical chemistry in all groups and histopathology of control and high-dose animals. Histopathology also was performed on all dead or moribund rats and on all that survived for 2 years. Average daily exposures were 11 to 150 mg/kg pyrilamine compared to human dosages up to 3 mg/kg. Pyrilamine treatment did not reduce survival. Final body weights were reduced relative to controls (mid-dose males, 93%, females, 82%: high-dose males, 82%, females, 70%). The incidences of inflammation of the nasolacrimal duct (chronic in females; suppurative in males), liver cytoplasmic vacuolization (males), and the combination of animals with either liver basophilic or clear cell foci (males) tended to significantly increase with dose. Adrenal pheochromocytomas, mammary gland fibroadenomas, and neoplasms of the clitoral gland, thyroid c-cell, and pituitary gland all tended to decrease with increasing dose in females. In males only preputial gland neoplasms exhibited a similar negative trend. While two ovarian granulosatheca cell benign tumors occurred in high-dose females, these were thought to be a random occurrence. There was no evidence for the carcinogenicity of pyrilamine in F344 rats in the current study.

Adrenal Medulla↗

PubMedDate not supplied

N-debenzylation of pyrilamine and tripelennamine in the rat. A new metabolic pathway.

Male Sprague-Dawley rats received 20 mg/kg of pyrilamine or tripelennamine intraperitoneally. The extract obtained from an enzymatically hydrolyzed urine was derivatized with or without Tri-Sil Z and analyzed by GC/MS. 2-(2-Dimethylaminoethyl)aminopyridine, 2-(4-hydroxybenzyl)aminopyridine, 2-[4-hydroxybenzyl-(2-dimethylaminoethyl)amino]pyridine, 2-[4-hydroxybenzyl-(2-methylaminoethyl)amino]pyridine, 2-[4-hydroxy-3-methoxybenzyl-(2-dimethylaminoethyl)amino]pyridine, and 2-[3-hydroxy-4-methoxybenzyl-(2-dimethylaminoethyl)amino]pyridine were detected as metabolites of pyrilamine. 2-(2-Dimethylaminoethyl)aminopyridine, 2-(alpha-hydroxybenzyl)aminopyridine, 2-[alpha-hydroxybenzyl-(2-dimethylaminoethyl)amino]pyridine, 2-[4-hydroxybenzyl-(2-dimethylaminoethyl)amino]pyridine, 2-[4-hydroxy-3-methoxybenzyl-(2-dimethylaminoethyl)amino]pyridine, and 2-[3-hydroxy-4-methoxybenzyl-(2-dimethylaminoethyl)amino]pyridine were detected as metabolites of tripelennamine. Thus, N-debenzylation of tripelennamine and N-demethoxybenzylation of pyrilamine occurs in vivo, through an intermediate of alpha-carbon oxidation and represents a new metabolic pathway for these compounds. The identity of the metabolite was confirmed by comparison with an authentic sample of 2-(2-dimethylaminoethyl)aminopyridine. The pharmacological implication of 2-(2-dimethylaminoethyl)aminopyridine, one of the metabolites of pyrilamine and tripelennamine, is discussed.

Aminopyridines↗

PubMed1977

Quantitative determinations of codeine phosphate, guaifenesin, pheniramine maleate, phenylpropanolamine hydrochloride, and pyrilamine maleate in an expectorant by high-pressure liquid chromatography.

The quantitative determinations of codeine phosphate, guaifenesin, pheniramine maleate, phenylpropanolamine hydrochloride, and pyrilamine maleate in a liquid dosage form are described. All active and inactive ingredients (sodium benzoate and FD&C Yellow No. 5 dye) can be separated with high-pressure liquid chromatography except the two antihistamines, pheniramine maleate and pyrilamine maleate. Pheniramine maleate is determined colorimetrically, and pyrilamine maleate is determined either by difference or spectrophotometrically. The methods are simple short, accurate, and precise. The standard deviations are reported.

Chromatography, High Pressure Liquid↗

PubMed1988

O-demethylation of pyrilamine.

O-Demethylation of pyrilamine with l-propanethiol and potassium tert-butoxide gave hydroxytripelennamine, one of the major metabolites of tripelennamine. The reaction of pyrilamine with other demethylating agents has been explored and the products formed have been characterized. The reaction of pyrilamine with 48% hydrobromic acid yielded 2-(2-dimethylaminoethyl)aminopyridine. When a mild, neutral demethylating agent, Me3Sil, was used, 2,3-dihydroimidazopyridinium iodide was the sole product formed.

Acids↗

PubMed1984

Chronic toxicity tests of pyrilamine maleate and methapyrilene hydrochloride in F344 rats.

Methapyrilene hydrochloride was administered at levels of 125 or 250 ppm in the diet to groups of male and female F344 rats. The closely analogous antihistaminic drug pyrilamine, as the maleate, was given at 2000 ppm in the diet or at 2 g/litre drinking-water to groups of male and female F344 rats. Almost all of the rats given the higher dose of methapyrilene had either carcinomas or neoplastic nodules of the liver, whereas at 125 ppm 40% of the rats had neoplastic nodules in the liver. Among the 20 male and 20 female rats treated with pyrilamine maleate mixed into the diet, two males and two females had hepatocellular carcinomas and, in addition, five males and eight females had neoplastic nodules in the liver. The incidence of liver neoplasms in the rats given pyrilamine in the drinking-water did not differ from that in the untreated controls, of which five males and three females had neoplastic nodules in the liver.

Aminopyridines↗

PubMedDate not supplied

Identification of pyrilamine metabolites by ammonia chemical ionization mass spectrometry.

The ammonia chemical ionization mass spectrometric analysis of pyrilamine, the N-oxide of pyrilamine, and related compounds is described. The use of ammonia as the reagent gas produced excellent [M + H]+ ions for these compounds. The suitability of this method for the analysis of two rat urinary metabolites of pyrilamine is demonstrated.

Aminopyridines↗

PubMed1990

Specific binding of [3H]pyrilamine to histamine H1 receptors in guinea pig brain in vivo: determination of binding parameters by a kinetic four-compartment model.

The binding of [3H]pyrilamine, a selective ligand of histamine H1 receptors, to guinea pig brain in vivo was compared with its binding to a brain homogenate. The pharmacological properties (regional distribution, saturability, and stereoselectivity) of the [3H]pyrilamine binding in vivo were similar to those of the in vitro binding to brain homogenate. A dynamic four-compartment model was proposed for the analysis of the kinetics of [3H]pyrilamine binding in vivo. The receptor constants in vivo were determined by a computer-fitting method after correcting the radioactivity of arterial plasma and brain for the presence of radioactive metabolites. The in vivo association and dissociation were 213 and 42 times, respectively, slower than those of in vitro binding at 37 degrees C. A possible mechanism for slow association and dissociation in vivo is discussed.

Aminopyridines↗

PubMed1995

Cardiac electrophysiological actions of the histamine H1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine.

We compared the cardiac electrophysiological actions of two types of H1-receptor antagonists--the piperidines, astemizole and terfenadine, and the nonpiperidines, chlorpheniramine and pyrilamine-in vitro in guinea pig ventricular myocytes and in vivo in chloralose-anesthetized dogs. Astemizole and terfenadine significantly increased action potential duration of guinea pig myocytes. This concentration-dependent prolongation of action potential duration was reverse frequency dependent and led to development of early afterdepolarizations, which occurred more frequently at higher concentrations and slower pacing frequencies. Astemizole and terfenadine potently blocked the rapidly activating component of the delayed rectifier, IKr, with IC50 values of 1.5 and 50 nmol/L, respectively. At 10 mumol/L, terfenadine but not astemizole blocked the slowly activating component of the delayed rectifier, IKs (58.4 +/- 3.1%), and the inward rectifier, IK1 (20.5 +/- 3.4%). Chlorpheniramine and pyrilamine blocked IKr relatively weakly (IC50 = 1.6 and 1.1 mumol/L, respectively) and IKs and IK1 less than 20% at 10 mumol/L. Astemizole and terfenadine (1.0 to 3.0 mg/kg IV) significantly prolonged the QTc interval and ventricular effective refractory period in vivo. Chlorpheniramine and pyrilamine (< or = 3.0 mg/kg) did not significantly affect these parameters. Block of repolarizing K+ currents, particularly IK1, by astemizole and terfenadine produces reverse rate-dependent prolongation of action potential duration and development of early afterdepolarizations, delays ventricular repolarization, and may underlie the development of torsade de pointes ventricular arrhythmias observed with the use and abuse of these agents.

Action Potentials↗