The biotransformation of [14C]lormetazepam in dogs,rabbits, rats and rhesus monkeys

1. After oral or intravenous doses (0.25?mg/kg) of [¹⁴C]lormetazepam to rats, most of the urinary radioactivity was associated with polar components and < 1% dose was excreted as unconjugated lormetazepam. About 30% of an oral dose was excreted in rat bile as a conjugate of lormetazepam and about 50% dose as polar metabolites. Plasma also contained mainly polar metabolites, and unchanged lormetazepam represented at most 10% of total plasma radioactivity after an oral dose.

2. Almost all the radioactivity in dog, rhesus monkey and rabbit urine, after oral or intravenous doses (0.5–0.7?mg/kg) of [¹⁴C]lormetazepam, was associated with conjugated material. In the dog there were only two major components, conjugates of lormetazepam and lorazepam (N-desmethyl-lormetazepam) which accounted for about 24% and 14% respectively of the oral dose in the 0–24?h urine. The same two conjugated components were also present in dog bile. Conjugated lormetazepam was the only major component in monkey and rabbit urine and accounted for about 60% dose in the 0–24?h urine of each species, while conjugated lorazepam accounted for only about 0.5% and 4% respectively.

3. Dog and monkey plasma contained mostly conjugated material after oral and intravenous doses (0.05–0.07?mg/kg of [¹⁴C]lormetazepam. Dog plasma after an oral dose contained conjugates of both lormetazepam and lorazepam with peak concn. at 1?h of 130 and 47 ng/ml respectively. Concn. of these conjugates in plasma declined with apparent terminal half-lives of about 17 and 27?h respectively after oral doses, and 13?h in both cases after intravenous doses. Conjugated lormetazepam was the only major component in monkey plasma representing a peak concn. of 180 ng/ml at 1?h after an oral dose, and declined with an apparent terminal half-life of about 11?h after oral or intravenous doses.

4. Lormetazepam crosses the placental ‘barrier’ of rabbits: its concn. in the foetus were similar to those in maternal plasma after intravenous doses.     

Disposition and metabolism of benoxaprofen in laboratory animals and man.

1. The absorption, distribution, metabolism and excretion of benoxaprofen, a novel anti-inflammatory compound, has been studied in the dog, mouse, rat, rabbit, rhesus monkey and man. 2. Benoxaprofen was well absorbed after oral administration of doses of 1 to 10 mg/kg in all six species. Only unchanged drug was detected in plasma. It was extensively bound to plasma proteins, the highest binding occurring in man (99.8%) and rhesus monkey (99.6%). 3. Species differences were observed in the plasma elimination half-life, the longest being in man (33 h). The rat and mouse also had high values (28 and 24 h respectively) whereas in the other species, values were less than 13 h. 4. After an oral dose of [14C]benoxaprofen (20 mg/kg) to female rats, tissue concn. was highest in liver, kidney, lungs, adrenals and ovaries. Tissue distribution in the pregnant rat was identical to the normal female. The compound was found in the foetus but at a concn. lower than in all maternal organs. 5. There was a marked species difference in the route of excretion. In man, rhesus monkey and rabbit, excretion in the urine was a major route, whilst biliary--faecal excretion was the only effective route in the rat and dog. 6. No major metabolic transformation of benoxaprofen was observed. Man and dog excreted the compound predominantly as the ester glucuronide whereas the rat, mouse, rabbit and rhesus monkey excreted a large proportion of the dose unchanged.     

Unusual metabolism of caffeine in the squirrel monkey

The chronic toxicity of caffeine observed with the squirrel monkey appears to be related to the long plasma half-life of caffeine in this species. A half-life of 11 hr was found following the administration of 5 mg/kg compared to 2.4 hr in the rhesus monkey (5 hr or less have previously been reported for the mouse, dog and man). The methylxanthines found in the tissues and urine of the squirrel monkey following caffeine administration were the same as those reported for other species. No difference in the metabolism of caffeine by a squirrel monkey showing a toxic response to 25 mg/kg/day and a monkey tolerating this dose could be determined. The squirrel monkey appears to have a unique deficit in its ability to catabolize caffeine to metabolites which can be effectively excreted.     

Pharmacokinetics of nisoldipine. I. Absorption, concentration in plasma, and excretion after single administration of [14C]nisoldipine in rats, dogs, monkey, and swine

The absorption, disposition and excretion of (+/-) 3-isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) have been studied following a single administration of the 14C-labelled compound to rats, dogs, monkey and swine via different routes (intravenous, oral, intraduodenal) in the dose range of 0.05-10 mg.kg-1. [14C]nisoldipine was absorbed rapidly and almost completely. Peak concentrations of radioactivity in plasma were reached 0.9 h (rat), 1.4 h (dog), and 3.6 h (monkey) after oral administration with normalized maximum concentrations being in the same range for all three species (0.49-0.79). The radioactivity was eliminated from plasma with half-lives between 42 h and 54 h within an observation period up to 3 days. The contribution of unchanged [14C]nisoldipine to the concentration of total radioactivity in plasma was low after oral administration (between 0.5% (monkey) and 3.4% (dog) in the peak) indicating an extensive presystemic elimination of this compound. The bioavailability was estimated at 3.4% in rats and 11.7% in dogs. [14C]nisoldipine was highly bound to plasma proteins with free fractions of 0.9-2.9%. The excretion of the radioactivity via urine and feces/bile both after oral and intravenous administration of [14C]nisoldipine occurred rapidly and almost completely within 48 h in all species. Very small residues in the body were recovered at the end of the experiments in rats and dogs (less than 1.6% of the dose). The biliary/fecal route of excretion was preferred in rats, dogs and swine, whereas in monkey 76% of the dose was excreted renally.(ABSTRACT TRUNCATED AT 250 WORDS)     

Extensive biliary excretion of the sulfasalazine analogue, susalimod, but different concentrations in the bile duct in various animal species correlating to species-specific hepatobiliary toxicity.

Studies on biliary concentrations of susalimod were conducted in rat, dog and monkey to clarify the interspecies differences observed in toxicology studies with respect to hepatobiliary toxicity after long-term administration of the compound. Dose-related bile duct hyperplasia appeared only in dogs at doses > or =75 mg/kg/day, while in rats and monkeys it did not appear at doses up to 1500 and 2000 mg/kg/day respectively. Biliary excretion was investigated after intraduodenal administration of susalimod in anaesthetised animals. In addition excretion routes were determined by collecting urine and faeces following a radiolabelled intravenous dose. Susalimod was extensively excreted via the bile in all animal species, > or =90%, mainly as non-conjugated parent compound. However, the local concentrations in bile varied between the species. Highest concentrations were obtained in the dog. The bile/plasma concentration ratio was 3400 in the dog, 300 in the monkey and 50 in the rat. In the dog, bile duct concentrations of susalimod about 30,000 micromol/l was obtained at plasma concentrations approximately similar to those at which hepatobiliary toxicity occurred, while in rat and monkey the levels were < or =7000 micromol/l at plasma concentrations similar to those obtained at the highest doses in the toxicology studies. From these results supported by a previous biliary excretion study in conscious dogs with chronic bile fistula receiving repeated administration of susalimod (P?hlman et al. 1999), it is likely that the hepatotoxic findings in dog are induced by the high concentrations of susalimod in the bile duct.     

Extensive Biliary Excretion of the Sulfasalazine Analogue,Susalimod, but Different Concentrations in the Bile Duct in Various Animal Species Correlating to Species-Specific Hepatobiliary Toxicity

Abstract: Studies on biliary concentrations of susalimod were conducted in rat, dog and monkey to clarify the interspecies differences observed in toxicology studies with respect to hepatobiliary toxicity after long-term administration of the compound. Dose-related bile duct hyperplasia appeared only in dogs at doses ≥75 mg/kg/day, while in rats and monkeys it did not appear at doses up to 1500 and 2000 mg/kg/day respectively. Biliary excretion was investigated after intraduodenal administration of susalimod in anaesthetised animals. In addition excretion routes were determined by collecting urine and faeces following a radiolabelled intravenous dose. Susalimod was extensively excreted via the bile in all animal species, ≥90%, mainly as non-conjugated parent compound. However, the local concentrations in bile varied between the species. Highest concentrations were obtained in the dog. The bile/plasma concentration ratio was 3400 in the dog, 300 in the monkey and 50 in the rat. In the dog, bile duct concentrations of susalimod about 30,000 μmol/l was obtained at plasma concentrations approximately similar to those at which hepatobiliary toxicity occurred, while in rat and monkey the levels were ≤7000 μmol/l at plasma concentrations similar to those obtained at the highest doses in the toxicology studies. From these results supported by a previous biliary excretion study in conscious dogs with chronic bile fistula receiving repeated administration of susalimod (Påhlman et al. 1999), it is likely that the hepatotoxic findings in dog are induced by the high concentrations of susalimod in the bile duct.     

Study on metabolism of pyridonecarboxylic acid II. Determination of metabolites of (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262) in blood, urine, bile, and feces

The fate of (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl-1,4- dihyro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262) was studied using T-3262 and 14C-T-3262 in various animals. 1. Metabolites in serum and urine were assayed for mouse, rat, rabbit, dog and monkey following oral administration of T-3262. In serum, besides unchanged T-3262 base, T-3262A (N-acetylated) was detected in rat, rabbit and monkey; T-3262B (deamino-hydroxylated) was detected in monkey. In urine, unchanged T-3262 base was excreted mainly. But a few of metabolites (T-3262A, T-3262B, T-3262 glucuronide, T-3262A glucuronide, T-3262B glucuronide, and unknown compound M-1) were detected, and species difference existed in types of metabolites. 2. Metabolites in bile and feces were assayed for mouse and rat following oral administration of T-3262 and 14C-T-3262. Metabolites in bile were similar to the urine, but the volume of T-3262A and T-3262A glucuronide was larger than in urine. In feces, the excreted compounds mainly consisted of unchanged T-3262 base. 3. p-Toluenesulfonic acid, which is the counter acid for T-3262 base, was absorbed following the oral administration of T-3262, and excreted in urine in the unchanged form.     

Metabolism of arylacetic acids. 1. The fate of 1-naphthylacetic acid and its variation with species and dose.

1. [Carboxy-14C]-1-Naphthylacetic acid has been administered to man, 6 primate species and 4 other mammalian species and the urinary metabolites examined by radiochromatogram scanning and reverse isotope dilution. Animals all received a dose of 100 mg/kg and man received 5 mg, orally. 2. Most species excreted at least 60% of the 14C in the urine in 48 h. Unchanged acid was a minor (0-17% dose) excretion product in all species except the cynomolgus monkey (35%). 3. In man, in 24 h 95% of 14C was excreted as 1-naphthylacetyl-glucuronide and 5% as 1-naphthylacetyltaurine. 4. 1-Naphthylacetylglucuronide was the major excretion product in all species except the bushbaby (21% dose) and the cat, which did not form this conjugate. 5. 1-Naphthylacetylglutamine was formed only by the cynomolgus, squirrel and capuchin monkeys and marmoset, and in no case accounted for more than 3% dose. 6. 1-Naphthylacetylglycine was found in the urines of 4 primate and 3 non-primate species, and was the major metabolite in the squirrel monkey, bushbaby and cat. 7. 1-Naphthylacetyltaurine was excreted by all species except the rabbit and the fruit bat. It was a major excretion product in the squirrel and capuchin monkeys, the marmoset and the cat. 8. The influence of dose on the pattern of metabolism and excretion of 1-naphthylacetic acid has been investigated in the rat.     

UDP glucuronyltransferase and phenolsulfotransferase from rat liver in vivo and in vitro—IV: Species differences in harmol conjugation and elimination in bile and urine in vivo

Harmol, (7-hydroxy-1-methyl-9H-pyrido-3,4b)-indol, is converted to harmol-sulfate and harmol-glucuronide when it is injected in vivo in the rat. Conjugation of harmol, and elimination of the conjugates in bile and urine were studied in cat, rabbit, mouse, guinea-pig and rat after an intravenous dose of 20 μmoles/kg. Rabbit and guinea-pig nearly exclusively glucuronidated harmol. The cat predominantly synthesized harmol-sulfate but harmol-glucuronide was also produced. Mouse and rat synthesized both conjugates to comparable amounts. After 2 hr about 20% of the dose was found in urine in the form of the conjugates. From 30–60% of the dose was present in bile after this time; the rabbit excreted only 9% in that time in bile and was a poor excretor in bile. The glucuronide conjugate is excreted to a higher extent in bile than the sulfate conjugate. The data suggest that biliary excretion requires a high liver concentration of the relevant compound for a high rate or excretion.     

4,4′-Dichlorobiphenyl: Distribution,metabolism, and excretion in the dog and the monkey

The tissue distribution, metabolism, and excretion of 4,4′-dichlorobiphenyl (4,4′-DCB) were investigated in beagle dogs and cynomolgus monkeys (Macaca fascicularis). Following a single iv dose of [¹⁴C]4,4′-DCB (0.6 mg/kg) excreta, blood, and tissues were collected at time intervals ranging from 15 min to 28 days for determination of levels of parent compound and its metabolites. Elimination of the parent PCB in the blood of both species was biphasic with a terminal-phase elimination rate constant of 0.018 hr^?1 for the dog and 0.002 hr^?1 for the monkey. By 24 hr the dog excreted 50% of the dose in the feces (43%) and the urine (7%). The percentage dose remaining was found largely as parent compound in the fat with some in muscle and skin. By 5 days 90% of the dose was excreted. In contrast, during the first 24 hr the monkey excreted less than 15% of the dose with less than 1% in the feces. The percentage dose remaining in the body was localized as parent compound in fat (33%) with lesser amounts in skin and muscle. By 28 days 59% of the dose was excreted, primarily in the urine. In anesthetized dogs 33% of the dose was excreted into the bile within 2 hr, while the monkey excreted only 0.4% of the dose by that route. The data present a clear species variation between the dog and the monkey in both the rate and route of excretion of 4,4′-DCB.     

2,3,6,2′,3′,6′-Hexachlorobiphenyl: Distribution,metabolism, and excretion in the dog and the monkey

The tissue distribution, metabolism, and excretion of 2,3,6,2′,3′,6′-hexachlorobiphenyl (236-HCB) were investigated in beagle dogs and cynomolgus monkeys (Macaca fascicularis). Following a single iv dose of [¹⁴C]236-HCB (0.6 mg/kg) excreta, blood, and tissues were collected at time intervals ranging from 15 min to 15 days for determination of levels of parent compound and its metabolites. Elimination of the parent PCB in the blood of both species was biphasic with a terminal-phase elimination rate constant of 0.23 day^?1 for the dog and 0.15 day^?1 for the monkey. By 24 hr the dog excreted 52% of the dose; 41% in the feces; 11% in the urine. The percentage dose remaining was found largely in liver, muscle, fat, and skin. By 3 days 70% of the dose was excreted. During the first 24 hr the monkey excreted 19% of the dose with about equal amounts appearing in urine and feces. The percentage dose remaining in the body was localized as parent compound in fat (15%) with lesser amounts in skin, muscle, and liver. By 15 days 61% of the dose was excreted, primarily in the feces. In anesthetized dogs 26% of the dose was excreted into the bile within 2 hr, while anesthetized monkeys excreted only 2.4% of the dose by that route. The data present a clear species variation between the dog and the monkey in the rate of metabolism of 236-HCB and its subsequent excretion via the bile.     

The metabolism of 5,5'-methylenedisalicylic acid in various species

Commercial methylenedisalicylic acid has been shown to be grossly impure. Pure 5,5′-methylendisalicylic acid (4,4′-dihydroxydiphenylmethane-3,3′-dicarboxylic acid) has been prepared and labelled with ¹⁴C. The fate of the pure compound in the rat, mouse, hamster, rhesus monkey, rabbit, guinea-pig and chicken has been investigated. The compound is excreted entirely unchanged in the urine and faeces in all the above species and no metabolites have been found. The biliary excretion of the injected compound is high (50–60%) in the rat and dog and low (5%) in the guinea-pig and rabbit. In the monkey, rabbit and guinea-pig, the compound is excreted almost exclusively in the urine. In the rat about 50% of the dose is excreted in the faeces. In the mouse and hamster, the main route of excretion is the urine, about 10% appearing in the faeces.     

2,4,5,2',4',5'-Hexachlorobiphenyl: distribution, metabolism, and excretion in the dog and the monkey

The tissue distribution, metabolism, and excretion of 2,4,5,2′,4′,5′-hexachlorobiphenyl (2,4,5-HCB) were investigated in beagle dogs and cynomolgus monkeys (Macacca fascicularis). Following a single iv dose of [¹⁴C]2,4,5-HCB (0.6 mg/kg), excreta, blood, and tissues were collected at time intervals ranging from 30 min to 15 days for dogs and 2 hr to 90 days for monkeys. The concentration of 2,4,5-HCB and its metabolites was determined in all samples. Elimination of the parent PCB from the blood of both species was biphasic with a terminal phase elimination rate constant of 0.045 day^?1 for the dog and 0.015 day^?1 for the monkey. By 15 days the dog had excreted 66% of the dose, 63% in the feces, and 3% in the urine. The percentage dose remaining was found largely as parent compound in the adipose tissue (16%), skin (6%), and muscle (2%). By 90 days, the monkey had excreted only 18% of the dose (17% in feces, 1% in urine). Again, the major storage depots for nonexcreted dose were adipose tissue 945%) and skin (5%). In anesthetized dogs, 0.8% of the dose appeared in the bile within 2 hr, while only 0.2% of the dose appeared in the bile of anesthetized monkeys in 2 hr. The monkey excreted a greater percentage of dose as parent compound into the bile than the dog. The data provide evidence that the pharmacokinetic behavior of 2,4,5-HCB in the monkey is similar to that observed in other species. However, the dog is unique from other species in that it can readily eliminate 2,4,5-HCB.     

Pharmacokinetics of nisoldipine. III. Biotransformation of nisoldipine in rat, dog, monkey, and man

After intraduodenal administration of 14C-labelled (+/-) 3-isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) to rats approx. 68% of the dose was excreted in the bile in the first 6 h. In an isolated perfused rat liver model the excretion with the bile was 56% of the total dose within 3 h. The recovery of radioactivity from orally administered [14C] nisoldipine was approx. 32% (rat), 23% (dog), 73% (monkey) and 74% (man), resp., in the urine. The unchanged drug was neither detected in the urine nor in the bile, but nisoldipine was present in plasma of the rat 30 min after dosing and up to 24 h in man. The drug was extensively metabolized: 18 biotransformation products were identified by comparison with synthetic reference compounds using combined GC-MS, 1 NMR-spectroscopy, mass spectrometry, gas chromatography/radio-gas chromatography and two-dimensional thin layer chromatography, 6 of them being quantitatively important (about 80% of the radioactivity excreted in urine). The metabolites identified accounted for approx. 82% (rat: bile and urine), 19% (dog, due to the low renal excretion), 58% (monkey: urine) and 64% (man: urine) of the excreted dose, resp. The following biotransformation steps occurred: hydroxylation of the isobutyl moiety, dehydrogenation of the 1,4-dihydropyridine system, oxidative ester cleavage, hydroxylation of one of the methyl groups in 2- or 6-position and subsequent oxidation to the carboxylic acid, oxidation of one of the methyl groups of the isobutyl moiety to the carboxyl group reduction of the aromatic nitro group (minor biotransformation reaction) and glucuronidation as phase II reaction.     

Metabolism of Arylacetic Acids: 1. The Fate of 1-Naphthylacetic Acid and its Variation with Species and Dose

1. [carboxy-¹⁴C]-1-Naphthylacetic acid has been administered to man, 6 primate species and 4 other mammalian species and the urinary metabolites examined by radiochromatogram scanning and reverse isotope dilution. Animals all received a dose of 100?mg/kg and man received 5 mg, orally.

2. Most species excreted at least 60% of the ¹⁴C dose in the urine in 48 h. Unchanged acid was a minor (0-17% dose) excretion product in all species except the cynomolgus monkey (35%).

3. In man, in 24?h 95% of ¹⁴C was excreted as 1 -naphthylacetyl-glucuronide and 5% as 1-naphthylacetyltaurine.

4. 1-Naphthylacetylglucuronide was the major excretion product in all species except the bushbaby (21% dose) and the cat, which did not form this conjugate.

5. 1-Naphthylacetylglutamine was formed only by the cynomolgus, squirrel and capuchin monkeys and marmoset, and in no case accounted for more than 3% dose.

6. 1-Naphthylacetylglycine was found in the urines of 4 primate and 3 non-primate species, and was the major metabolite in the squirrel monkey, bushbaby and cat.

7. 1-Naphthylacetyltaurine was excreted by all species except the rabbit and the fruit bat. It was a major excretion product in the squirrel and capuchin monkeys, the marmoset and the cat.

8. The influence of dose on the pattern of metabolism and excretion of 1-naphthylacetic acid has been investigated in the rat.     

Pharmacokinetics of fominoben-HCl in the dog and the rabbit (author's transl)]

The pharmacokinetics of 3'-chloro-2'-(N-methyl-N-[(morpholino-carbonyl)-methyl]-aminomethyl)benzanilide-hydrochloride (P-B 89 Cl, fominoben-HCl, Noleptan) was studied in dog and rabbit following a dose of 3 mg/kg on i.v. and p.o. administration of the 44C-labelled compound. Absorption: The compound is absorbed fast in the dog and very fast in the rabbit. Practically the entire dose is absorbed by the two species. Maximum levels in blood: dog 0.5 microgram/ml, rabbit 0.8 microgram/ml, in the plasma: dog 0.6 microgram/ml, rabbit 1.2 microgram/ml at 1--2 h p.a. and 15--30 min p.a. Elimination: The elimination from blood and plasma proceeds biphasically. 1st half-life: 1--2 h, 2nd half-life: 19--27 h (higher values for the rabbit). The dog eliminates preponderantly via the bile with the faeces, the rabbit via the kidneys: Dog: 19% in urine and 63% in faeces, rabbit 79% in urine and 16% in faeces, measured up to 96 h p.a. One rabbit excreted 70% via the urine up to 7 h p.a. The half-lives of urinary elimination are very well comparable with the figures for plasma. Biotransformation: Plasma (maximum level): Dog: Visible amounts of parent compound (M0), Rabbit: Traces M0, much M2. Urine (0--24 h p.a.): Dog: Traces: M0, Rabbit: Traces M0, much M2.     

Application of (1)H- and (19)F-NMR spectroscopy in the investigation of the urinary and biliary excretion of 3,5-, 2,4-ditrifluoromethylbenzoic and pentafluorobenzoic acids in rat

1. The metabolism and excretion of 2,4-, 3,5-ditrifluoromethyl- and pentafluorobenzoic acids were studied in the bile-cannulated rat using (1)H- and (19)F-NMR spectroscopy following intraperitoneal administration at 50 mg kg(-1). 2. Pentafluorobenzoic acid was excreted in the urine entirely unchanged. No detectable compound or metabolites were eliminated in the bile. A total of 63.5 +/- 6.7% of the dose was recovered in the 24-h collection period. 3. In the case of 2,4-ditrifluromethyl benzoic acid, 83.9 +/- 5.2% of the dose was recovered in the 24h after administration, with about 52% being excreted in the urine and 32% in the bile. The majority of the material present in the urine was unchanged parent compound. In bile, some 60% of the compound-related material excreted was present as transacylated ester glucuronide conjugates. 4. For 3,5-ditrifluoromethylbenzoic acid, 49.6 +/- 5.3% of the dose was recovered in the 24-h collection period, with about 22% being excreted in the urine and 28% in the bile. The material excreted in both the urine and bile was a mixture of the parent acid and transacylated ester glucuronides. 5. Urinary excretion in bile-cannulated animals was similar to that found in studies using non-cannulated animals dosed at 100mg kg(-1).     

Studies on the metabolic fate of 14C-rokitamycin. IV. Absorption, metabolism and excretion in dogs

Absorption, metabolism and excretion of rokitamycin (TMS-19-Q), were studied after oral (50 mg/kg), intraduodenal (50 mg/kg) and intravenous (10 mg/kg) administrations of 14C-TMS-19-Q to male dogs. Maximum blood and plasma concentrations of the drug reached at 2 hours after oral administration, and they were 11.1 and 14.3 micrograms/ml, respectively. Maximum blood and plasma concentrations reached at 30 minutes after intraduodenal administration, and they were 10.7 and 12.0 micrograms/ml, respectively. Blood and plasma concentrations at 3 minutes after intravenous administration were 8.4 and 11.1 micrograms/ml, respectively. At 24 hours, they were 0.6 and 1.7 micrograms/ml, respectively. During the first 72 hours period after oral administration, 12.8 and 82.6% of the dose were excreted in the urine and feces, respectively. A total recovery rate was 95.4% of the dose. During the first 72 hours period after intravenous administration, 19.4 and 75.3% of the dose were excreted in the urine and feces, respectively. A total recovery rate was 94.7% of the dose. During the first 24 hours period after intraduodenal administration, 18.0 and 48.3% of the dose were excreted in the urine and bile, respectively. A total recovery rate was 66.3% of the dose. Major metabolic reactions on TMS-19-Q were deacylation and hydroxylation, and the major metabolites of TMS-19-Q found in the plasma urine and bile after intraduodenal administration to dogs were 10"-OH-TMS-19-Q, LM A7, LM V and 14-OH-LM V.     

Pharmacokinetics of ciprofloxacin. 1st communication: absorption, concentrations in plasma, metabolism and excretion after a single administration of [14C]ciprofloxacin in albino rats and rhesus monkeys

The absorption, disposition, metabolism and excretion of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-[U-14C]piperazinyl)-3- quinoline carboxylic acid (ciprofloxacin, Bay o 9867; designated tradename: Ciprobay) were studied following a single intraduodenal (rat), oral and intravenous (rat, monkey) administration, respectively, in the dose range 5 to 30 mg/kg body weight. Ciprofloxacin was absorbed partially (30 to 40%) in both species. Peak plasma concentrations of radioactivity were measured approximately 1 h (rat) or 2 h (monkey) after oral dosing. Terminal half-lives ranging from 26 to 44 h were determined for the elimination of radioactivity from the plasma (observation time up to 48 h after dosing). Nearly identical concentrations of the unchanged drug and total radioactivity were found during the first 7 or 8 h for the monkey after intravenous injection and for the rat also after oral administration, respectively. After reaching maximum concentration of 0.25 microgram/ml after administration of 5 mg/kg to rats and 0.88 microgram/ml after dosing with 30 mg/kg to a rhesus monkey, the unchanged drug was eliminated from plasma corresponding to half-lives ranging from 3 h (rat) and 4.4 h (monkey). The radioactivity was rapidly and completely excreted in both species. After intravenous administration about 51% (rat) and 61% (monkey), respectively, was excreted via the kidney. After oral dosing renal excretion amounted to 6-14% (rat) and 30% (monkey), respectively. Maximum residues in the body (exclusive gastrointestinal tract) of 1% of dose occurred in both species. In urine and feces of rats predominantly the unchanged drug and a conjugate were detected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism of arylacetic acids. 2. The fate of [14C]hydratropic acid and its variation with species.

1. (+/-)-[methyl-14C]-Hydratropic acid was administered to man, rhesus monkey, cat, rabbit and fruit bat. 2. All species excreted 60-100% of administered 14C in the urine in 24 h, and unchanged hydratropic acid accounted for 0-17% of the dose. 3. In man, the urinary 14C consisted of a very small quantity (1%) of unchanged hydratropic acid with the remainder as hydratropylglucuronide. 4. Hydratropylglucuronide was the major urinary excretion product in the 4 animal species, while the glycine conjugate was present in the urine of cat and rat. Additionally, cats excreted the taurine conjugate of hydratropic acid. 5. Bile-duct cannulated rats excreted 20-30% of an injected dose of [14C] hydratropic acid in the bile in 3 h mainly as hydratropylglucuronide.