On the terrestrial toxicity of the fungicide imazalil (enilconazole) to the earthworm species Eisenia foetida.

The toxicity of imazalil (enilconazole), of its sulfate salt, and of a principal environmental transformation product to the earthworm species Eisenia foetida was determined. The 48-hr contact test and the 14-day artificial soil test as described by OECD guideline 207 were carried out. Concentrations of the parent substance in earthworm tissues at the end of the exposure in soil were determined by gas chromatography. The LC50 of imazalil was 12.8 micrograms/cm2 in the contact test and 541 micrograms/g in the artificial soil test. The LC50 values of the sulfate salt were 11.6 micrograms/cm2 and 532 micrograms/g, respectively. The transformation product had a LC50 of 108 micrograms/cm2 in the contact test, and the survival in the soil test exceeded 90%, even at levels of 1000 micrograms/g. Tissue levels of imazalil in surviving worms were always lower than the concentrations in corresponding soil. The LC50 values largely exceeded the levels expected after normal use. Therefore, the fungicide is not considered to be harmful to earthworms in the soil environment.

Excretion and biotransformation of cisapride in dogs and humans after oral administration.

The excretion and biotransformation of cisapride, a novel gastrokinetic drug, were studied after a single po dose of [14C]cisapride in dogs and humans. The excretion of radioactivity amounted to 97% within 4 days after a 1 mg/kg dose in dogs (72% in feces and 25% in urine). After a 10-mg dose in humans, 44% was excreted in the 0-24-hr urine and 37% in the 0-35-hr feces; excretion was complete within 4 days. Excretion of the parent drug was greater in dogs (0.4-1.3% of the dose in urine, 23% in feces) than in humans (0.2% in urine, 4-6% in feces). This was due, at least in part, to a larger proportion of amine glucuronidation and sulfation in dogs. N-Deal-kylation at the piperidine nitrogen resulting in the main urinary metabolite, norcisapride, and aromatic hydroxylation of the 4-fluorophenyl ring were major metabolic pathways in both species. Norcisapride excretion accounted for 14% of the dose in dogs and 41-45% in humans. Minor metabolic pathways were O-dealkylation at the 4-fluorophenoxy group and piperidine oxidation. Peak plasma levels and AUC values of norcisapride in humans were 8-9 times lower than those of cisapride. Apart from more amine conjugation in dogs, the biotransformation of cisapride was similar in dogs and humans.

Excretion and biotransformation of cisapride in rats after oral administration.

The excretion and biotransformation of cisapride, a novel gastrokinetic drug, were studied after single (10, 40, and 160 mg/kg) and repeated (10 mg/kg/day) po administration to rats, using three different radiolabels. In fasted rats, cisapride was absorbed almost completely, except for the 160 mg/kg dose. Cisapride was metabolized extensively to at least 30 metabolites. The excretion of the metabolites amounted to more than 80% of the dose at 24 hr and was almost complete at 96 hr after dosing. In bile duct-cannulated rats, 60% was excreted in the bile within 24 hr, 45% of which underwent enterohepatic circulation. The main urinary metabolites, 4-fluorophenyl sulfate and norcisapride, primarily resulted from the N-dealkylation at the piperidine. Another major metabolic pathway was aromatic hydroxylation, occurring on either the 4-fluorophenoxy or the benzamide rings. The resulting phenolic metabolites were eliminated as conjugates in the bile; a large portion of them were subjected to a rapid enterohepatic circulation before their final excretion in the feces. Minor metabolic pathways included piperidine oxidation, O-dealkylation, O-demethylation of the methoxy substituent at the benzamide, and amine glucuronidation. Only minor quantitative dose- and sex-dependent differences could be observed for the mass balance of the metabolites. Upon repeated po dosing, steady state excretion rates were already attained after two to three doses, and excretion and metabolite patterns were very similar to those after single dose administration.

Excretion and biotransformation of alfentanil and sufentanil in rats and dogs.

The excretion and biotransformation of alfentanil (ALF) and sufentanil (SUF), two recent analogues of the synthetic opioid fentanyl, were studied after single iv administration of the tritium-labeled drugs in male rats and dogs. The drugs were almost completely metabolized in the two species, which resulted in a large number of metabolites. The excretion of the metabolites was rapid and exceeded 95% within 4 days, except for that of ALF metabolites in dogs (about 85%). For ALF, excretion of the radioactivity with the urine (73% in rats, about 76% in dogs) exceeded that with the feces. For SUF, excretion of the radioactivity with the urine amounted to 38 and 60% and that with the feces to 62 and 40%, in rats and dogs, respectively. Bile-cannulated rats excreted 68% with the bile within 24 hr after SUF dosing, and about 22% of this biliary radioactivity was subjected to enterohepatic circulation. After an ALF dose, the biliary excretion amounted to 24%, and the enterohepatic circulation was minimal. The main metabolic pathways of the two drugs were the oxidative N-dealkylation at the piperidine nitrogen and at the amide nitrogen, oxidative O-demethylation, aromatic hydroxylation, and the formation of ether glucuronides. N-[4-(Hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide (M6) was the main metabolite of both ALF and SUF in rats. In dogs, the glucuronide of N-(4-hydroxyphenyl)propanamide (M5) was the main metabolite of ALF. After SUF dosing in dogs, N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide was more abundant than M5.

Excretion and biotransformation of ketanserin after oral and intravenous administration in rats and dogs.

The excretion and biotransformation of ketanserin, a novel serotonin S2-receptor blocking agent used in hypertension and related diseases, were studied after single po (1 or 10 mg/kg) and iv (2.5 mg/kg) administration in rats and dogs, using two different radiolabels. Orally administered ketanserin was well absorbed and almost completely metabolized in both species. The excretion of the metabolites was rapid and amounted to about 90% within 4 days. In the various groups of rats and dogs, excretion of the radioactivity with the feces (48 to 67%) exceeded that with urine (27 to 43%). In po dosed bile-cannulated rats, 57% was excreted with the bile within 24 hr, whereas about 30 to 40% of the biliary radioactivity was subjected to enterohepatic circulation. The major urinary, biliary, and fecal metabolites were characterized by HPLC and mass spectrometric analysis. The main metabolic pathways of ketanserin were the aromatic hydroxylation at the quinazolinedione moiety, the oxidative N-dealkylation at the piperidine nitrogen, reduction of the ketone function and piperidine oxidation, followed by ring scission. The mass balance of the metabolites, as estimated by reversed-phase HPLC with on-line radioactivity detection, was very similar between male and female rats, as well as between rats po dosed at 10 mg/kg and iv dosed at 2.5 mg/kg. In rats, major urinary metabolites resulted from the N-dealkylation pathway, whereas hydroxyketanserin was the main biliary and fecal metabolite. In dogs, the N-dealkylation pathway was less abundant, whereas higher doses resulted in smaller relative amounts of hydroxylated metabolites and larger relative amounts of ketanserin-ol, resulting from the ketone reduction. Dog plasma levels of ketanserin-ol exceeded those of the parent drug from about 5 hr after po dosing.

Excretion and metabolism of lorcainide in rats, dogs and man.

After p.o. or i.v. administration of 3H-lorcainide, excretion of the radioactivity was almost complete within four days. In rats and dogs, about 35% of the dose was excreted in the urine and about 60% in the faeces. However, in humans, 62% was excreted in the urine and 35% in the faeces. In rats, about 70% of the orally administered radioactivity was excreted in the bile within 24 hours. Enterohepatic circulation was proven by "donor-acceptor" coupling in rats. Lorcainide was extensively metabolized. Urinary and faecal metabolites were isolated by extraction and high pressure liquid chromatography (HPLC), and characterized by chromatographic comparison with reference compounds, by mass spectrometry, and NMR. The mass balance for unchanged lorcainide and its major metabolites (determined by radio-HPLC) was very similar in the urine and faeces. Only minor quantitative differences were observed between intravenously and orally dosed animals, and between male and female rats. Major biotransformation pathways in the three species were: hydroxylation, O-methylation and glucuronidation. 4-Hydroxy-3-methoxy-lorcainide was the main metabolite. alpha-Oxidation resulting in alpha, 4-dihydroxy-3-methoxy-lorcainide, was observed in dogs only. Minor pathways were: oxidative N-dealkylation and amide hydrolysis. A remarkable 5-hydroxy-3,4-dimethoxy-metabolite was identified unambiguously in the three species.

Excretion and metabolism of flunarizine in rats and dogs.

The excretion and metabolism of (E)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propenyl)piperazine dihydrochloride (flunarizine hydrochloride, R 14 950, Sibelium) were studied after single oral doses in rats and dogs, using tritium-labelled as well as 14C-labelled drug. Flunarizine was well absorbed in both species. The mass balance for the unchanged drug and its major metabolites in urine, bile and faeces, as estimated with radio-HPLC, ALLOWED an explanation of the differences observed for the excretion pattern of the radioactivity in flunarizine-14C and flunarizine-3H dosed rats, and in male and female rats. Main metabolic pathway in male rats was the oxidative N-dealkylation resulting in bis(4-fluorophenyl)methanol and a number of complementary metabolites of the cinnamylpiperazine moiety, of which hippuric acid was the main one. In female rats and male dogs, however, hydroxy-flunarizine was the main metabolite, resulting from the aromatic hydroxylation of the phenyl ring of the cinnamyl moiety. Enterohepatic circulation of bis(4-fluorophenyl)methanol and hydroxy-flunarizine was proved by "donor-acceptor" coupling in rats; in bile and urine, these two metabolites were present mainly as glucuronides. The glucuronide of hydroxy-flunarizine was also the main plasma metabolite in dogs.

On the pharmacokinetics of domperidone in animals and man III. Comparative study on the excretion and metabolism of domperidone in rats, dogs and man.

The excretion and metabolism of the novel gastrokinetic and antinauseant drug domperidone were studied after oral administration of the 14C-labelled compound to rats, dogs and man, and after intravenous administration to rats and dogs. Excretion of the radioactivity was almost complete within four days. In the three species, the radioactivity was excreted for the greater part with the faeces. Biliary excretion of the radioactivity amounted to 65% of the dose 24 hours after intravenous administration in rats. Unchanged domperidone as determined by radioimmunoassay, accounted in urine for 0.3% in dogs, 0.4% in man, and in faeces for 9% in dogs and 7% in man. The main metabolic pathways of domperidone in the three species were the aromatic hydroxylation at the benzimidazolone moiety, resulting in hydroxy-domperidone -the main faecal metabolite-, and the oxidative N-dealkylation at the piperidine nitrogen, resulting in 2,3-dihydro-2-oxo-1H-benzamidazole-1-propanoic acid the major radioactive urinary metabolite- and 5-chloro-4-piperidinyl-1,3-dihydro-benzimidazol-2-one. In urine the two first metabolites were present partly as conjugates. A mass balance for the major metabolites in urine, faeces, bile and plasma samples was made up after radio-HPLC (reverse-phase HPLC with on-line radioactivity detection) of various extracts. Only minor species differences were detected.