Separation and identification of phase I and phase II [14C]antipyrine metabolites in rat and dog urine.

A simple and accurate HPLC procedure was developed to quantify, in a single run, all phase I and phase II [14C]antipyrine metabolites that occur in rat and dog urine. All metabolites were subjected to thermospray-LC-MS and EI-MS in order to establish their structure. The rat metabolizes antipyrine to eight major metabolites, six of which are conjugated; 1.4% of the dose was excreted unchanged, 18.9% in a free form, 30.6% as sulfates and 21.1% as glucuronides. The dog metabolizes antipyrine to four metabolites, all as sulfate (61.0% of the dose) or glucuronide conjugates (16.2% of the dose).

[The disposition of bornaprine hydrochloride in the rat. 2. The metabolism of exo-epimers]. / Zur Disposition von Bornaprin-hydrochlorid bei der Ratte. 2. Mitteilung: Untersuchungen zum Metabolismus des Exo-Epimeren.

The biotransformation of an epimeric form of the anticholinergic drug exo-2-phenyl-bicyclo-[2.2.1.]-heptane-2-carboxylic acid (4'-diethylaminopropyl)ester hydrochloride (bornaprine hydrochloride, Sormodren) was investigated after oral application in male Wistar rats. Main metabolite of the exo-isomer in the feces was the hydroxylated and sulfate-conjugated product, substitution having occurred at C(5) of the bicyclic ring in exo-position. As further metabolites, the sulfate-conjugate in exo-position at C(6) and the N-desethyl derivatives of both were detectable.

Metabolism of the calcium antagonist gallopamil in man.

The metabolism of gallopamil (5-[(3,4-dimethoxyphenyl)methylamino]-2-(3,4,5-trimethoxyphenyl) -2- isopropylvaleronitrile hydrochloride, Procorum, G) was studied after single administration (2 mg i.v., 50 mg p.o.) of unlabelled and labelled G (14G, 2H). TLC, HPLC, GLC, MS and RIA were used for assessment of G and its metabolites in plasma, urine and faeces. G clearance is almost completely metabolic, with only minimal excretion of unchanged drug. Metabolites represent most of the plasma radioactivity after p.o. administration. They are formed by N-dealkylation and O-demethylation with subsequent N-formylation, or glucuronidation, respectively. Compound A, derived by loss of the 3,4-dimethoxyphenethyl moiety of G is the main metabolite in plasma and urine (about 20% of the dose). This metabolite is accompanied by its N-formyl derivative (C), by the N-demethylated compound (H) and the acid (F), formed by oxidative deamination of A. Only 3 unconjugated monphenoles from several O-demthylated products showed distinct plasma levels which were nevertheless lower than metabolite A. These metabolites had no relevance to the pharmacodynamic action. Conjugated monophenolic and diphenolic products represented the major part in plasma and were excreted predominantly via the bile: they represented almost the whole faecal metabolite fraction. Less than 1% of the dose was recovered unchanged in the urine. About 50% of the dose is excreted by urine and 40% by faeces.

[The disposition of bornaprine hydrochloride in the rat. 1. Pharmacokinetics: synthesis, plasma level and elimination]. / Zur Disposition von Bornaprin-Hydrochlorid bei der Ratte. 1. Mitteilung: Untersuchungen zur Pharmakokinetik: Synthese, Plasmaspiegel und Elimination.

The biliary elimination and plasma concentration-time course of radioactivity and unchanged compound of 2-phenyl-bicyclo-[2.2.1]- heptane-2-carboxlylic acid (4'-diethylamino-propyl)ester hydrochloride (bornaprine hydrochloride, Sormodren) were investigated after oral application in Wistar rats. The curves showed no obvious differences in their pharmacokinetic properties.

Studies on the metabolism of propafenone. 3rd Comm.: Isolation of the conjugated metabolites in the dog and identification using fast atom bombardment mass spectrometry.

The metabolism and urinary and biliary excretion of propafenone (2-(2'-hydroxy-3'-propylamino-propoxy)-omega-phenyl-propiophenone hydrochloride) were studied in the dog. Approximately 20% of the dose was excreted in 24 h with the urine and about 65% with the bile. Propafenone was extensively metabolized. Less than 4% of the dose was recovered unchanged in urine and bile. The metabolites were mainly excreted as conjugates. Free metabolites accounted for less than 20% of the dose. Separation methods were developed to isolate and purify the conjugated metabolites. Fractionation on an Al2O3-column yielded a sulphate and a glucuronide fraction, further separation and purification was done by TLC and HPLC. Positive and negative ion fast atom bombardment mass spectra (FAB/MS) were obtained of the purified glucuronides. The structures of two hydroxylated propafenone derivatives and two O-methylated catechol-like derivatives were definitely proven by FAB/MS, the glucuronic acid moiety being conjugated to the hydroxyl function in the different aromatic rings. Two isomeric propafenone glucuronides were found in the bile, probably diastereomeric forms of the O-glucuronide. Thus FAB/MS proved to be a complementary method to electron impact ionization mass spectrometry (EI/MS) for studying drug metabolism. The structures of free and conjugated metabolites can be defined from the combination of both mass spectrometric techniques.

Studies on the metabolism of propafenone. 1st Comm.: synthesis and chromatographic/mass spectrometric properties of the labelled compound and of the reference substances.

The synthesis of 14C-propafenone and 2H-propafenone (propafenone: 2-(2'-hydroxy-3'-propylamino-propoxy)-omega-phenyl-propiophenone hydrochloride) and some reference compounds is described. The thin-layer chromatographic, high-performance liquid and gas chromatographic properties of the substances are described. Propafenone and the reference substances were studied by mass spectrometry and compared with each other, with respect to structural elucidation of the metabolites. The chromatographic and mass spectrometric data (key ions) enables the metabolites of propafenone to be identified in biological material.

Studies on the metabolism of propafenone. 2nd comm.: studies on the biotransformation in the dog.

Following administration of 14C- and 2H-labelled propafenone hydrochloride (2-(2'-hydroxy-3'-propylaminopropoxy)-omega-phenyl-propiophenone hydrochloride) to beagle dogs, the metabolites were isolated from urine and bile and analysed by mass spectrometry. Reference substances were synthesized on the basis of the structures postulated from the mass spectra and compared with the substances isolated from the biological material. Propafenone was absorbed completely following i.d. administration and eliminated mainly with the bile. Within 28 h 10% of the dose was excreted with the urine and 87% with the bile. Propafenone was extensively metabolized. Less than 1% of the dose was recovered as unchanged substance in urine and bile. The urinary and biliary metabolites were almost exclusively conjugated. The main metabolite, accounting for more than 30% of the dose, was propafenone glucuronide, followed by conjugates of hydroxylated propafenone derivatives with glucuronic acid and sulphuric acid. 5-Hydroxy-propafenone, a propafenone derivative hydroxylated in the middle aromatic ring, and a derivative hydroxylated in the omega-phenyl ring each accounted for about 15% of the dose. Besides these monohydroxy metabolites, two other O-methylated catechol-like derivatives, substituted in the different aromatic rings were recovered. The remainder of the metabolic products identified were mainly substances resulting from degradation of the propoxyamine side chain.

[Studies on the disposition of meproscillarin in rat and dog (author's transl)]. / Untersuchungen zur Disposition von Meproscillarin an den Spezies Ratte und Hund.

The disposition of 14-hydroxy-3beta-[(4-O-methyl-alpha-L-rhamnopyranosyl)oxy]-14beta-bufa-4,20,22-trienolide (meproscillarin, Clift) formed by methylation of proscillaridin was tested in rats and dogs. Meproscillarin is better absorbed than proscillaridin. The drug is primarily eliminated via the bile. After oral administration 6% of the dose were excreted with urine by the rat and 3% by the dog. The main metabolite in the bile was shown to be a glucuronide of meproscillarin.