Enterohepatic circulation of radioactivity following an oral dose of [14C]temazepam in the rat

The enterohepatic circulation of radioactive material after administering [14C]temazepam was evaluated in three sets of male Wistar strain rats connected in pairs by bile duct-duodenum cannulae. After a single oral dose (10 mg kg-1) to the donor rat, the excretion of radioactivity in the urine and faeces of both rats and in the bile of the recipient rat was determined. Mean total recovery of the administered radioactivity was 92.2%. Based on the amount remaining in the donor rat (gastrointestinal tract and faeces), 81.7% of the dose was absorbed by the donor. The total amount recovered from the recipient, 69.4% of original dose (85.1% of donor's absorbed dose), represented the amount excreted in the donor's bile. Similarly, 54.1% of the original dose (77.9% of the transferred biliary excretion from donor) was reabsorbed by the recipient, and the biliary excretion from this animal (45.9% original dose) accounted for 86.% of the amount reabsorbed.     

Disposition and metabolism of radiolabelled pentachloroanisole in rats and rabbits

Male Sprague-Dawley rats and New Zealand White rabbits were administered ¹⁴C-labelled pentachloroanisole (PCA) in corn oil by gavage as single doses of 25 mg/kg and were then placed in individual metabolism cages for as long as 4 days. Peak blood level of radioactivity occurred 6 hr after administration of the dose to rats and between 3 and 4 hr in rabbits; the blood elimination half-life ranged from 8 to 15 hr in rats and averaged 6 hr in rabbits. Rats excreted an average of 54.2% of the administered radiolabel in the urine and 32.4% in the faeces during the 96 hr following the dose; rabbits excreted an average of 84.2 and 13.1% of the radiolabel in the urine and faeces, respectively, during this time. Examination of the metabolites in the rat showed that 60% of the urinary radioactivity was attributable to tetrachlorohydroquinone (TCH). 3% to free pentachlorophenol (PCP) and 29% to conjugated PCP; faecal metabolites were PCP (85.7%), TCH (4.3%) and polar metabolite(s) (10%). In the rabbit, 58% of the urinary radioactivity was attributable to TCH. 8% to free PCP and 34% to conjugated PCP. Faecal metabolites consisted of PCP and conjugated material.     

Tissue distribution and elimination of [3H]levamisole in the rat after oral and intramuscular administration

Total radioactivity and drug concentrations were determined in plasma, organs and excreta of male rats given a single oral or intramuscular dose (7.5 mg/kg) of [3H]levamisole. The anthelmintic drug was distributed mostly within the digestive contents after oral administration and in kidneys and liver after intramuscular injection. The parent drug accounted only for 32 to 45% of total radioactivity in plasma and it appeared metabolized in both urine and bile. The urine (0-72 h) contained 68-78% of the radioactive dose, as parent drug and other tritiated materials. The 4-hydroxylation of levamisole did not represent a major metabolic pathway of the drug in the rat.     

Glutathione conjugate formation from hexachlorocyclohexane and pentachlorocyclohexene by rat liver in vitro

1. Metabolites of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were extracted from the bile of TCDD-treated dogs and administered by gavage to bile-duct-cannulated rats and also to an intact rat.

2. Radioactivity of the TCDD metabolites was rapidly cleared from the body of the rats, indicating that bioaccumulation of these compounds does not occur.

3. Biliary excretion was the most important route of elimination in the cannulated rats and amounted to > 30% of the administered dose within 24h. TCDD metabolites were also eliminated to a minor extent by the kidneys. The combined recovery of radioactivity in faeces, bile and urine after 24h accounted for >85% of the dose.

4. The intact animal exhibited a somewhat different kinetic behaviour in that only 13% dose was excreted in faeces and urine after 24h, which indicates enterohepatic circulation. The administered radioactivity was completely recovered after 72?h.

5. Results from the present experiments indicate that metabolism of TCDD is the ratelimiting step in elimination of TCDD from the liver. Interspecies variability in the toxicity of TCDD may in part be attributable to different rates at which the species metabolize and excrete TCDD.     

Absorption studies with the anti-diarrhoeal agent ethacridine lactate in laboratory animals and man

Tritiated 2-ethoxy-6,9-diaminoacridine (ethacridine lactate, Rivanol) has been orally administered to rat, dog, rabbit and man, and the distribution of radioactivity between urine and faeces determined. Complete recoveries of radioactivity were obtained from rat, rabbit and man. From direct measurement of levels of radioactivity, the maximum percentage of the dose excreted via the urine varied from 1.7% (man) to 6.1% (dog). Tritiated water accounted for nearly 50% of this amount. The low levels of radioactivity in plasma of dog and man and in the bile of rats following administration of 3H-ethacridine lactate suggested that there was only a low degree of oral absorption and substantiated previous reports that the drug is essentially unabsorbed in man. From fluorimetric measurements and the determination of levels of radioactivity in ether extracts of urine, it could be concluded that for all species less than 0.1% of the dose appeared in the urine as acridine-like material.     

Absorption, distribution, and elimination of a single oral dose of [14C]tri-o-cresyl phosphate in hens

The absorption, distribution, elimination, and metabolism of a single oral dose of 50 mg (4.6 microCi)/kg of uniformly phenyl-labeled [14C]tri-o-cresyl phosphate (TOCP) was investigated in adult chickens. Three treated hens were killed at each time interval: 0.5, 1, 2, and 5 days. TOCP was absorbed from the gastrointestinal tract and subsequently distributed throughout the body. Generally, the highest concentrations of radioactivity were associated with gastrointestinal tract parts, bile, kidneys, liver, and lungs. Most of the radioactivity (47%) was excreted in the combined fecal-urinary excreta during the first 12 h. Very small fractions of the dose were deposited in egg albumen and egg yolk, 0.12% and 0.24%, respectively during the 5-day study. After 5 days, 99% of the dose was eliminated in excreta. TOCP and its metabolites in bile and the combined fecal-urinary excreta were analyzed by high-performance liquid chromatography and liquid scintillation spectrometry. TOCP and nine of its metabolites were identified. In the bile a TOCP active metabolite, saligenin cyclic-o-cresyl phosphate, was the predominant compound found compared to the parent compound in the excreta. These results suggest that in the hen TOCP is excreted slower than the rat and also undergoes metabolic activation. The absorption, elimination, and metabolic profile of TOCP in the hen may contribute to its sensitivity to delayed neurotoxicity.     

Tissue distribution and elimination of 14C-aminoglutethimide in the mouse

Following oral administration of 14C-aminoglutethimide (Orimeten), male mice excreted 75% and female mice 59% of the administered dose during 24 h. After 72 h, elimination was essentially complete in male mice, whilst recovery from female mice was 74%. As assessed by quantitative assay and whole-body autoradiography, a wide distribution of radioactivity was found with high concentrations of radioactivity occurring only in the bile, gastro-intestinal tract and liver at early times. Residual (72 h) tissue levels of radioactivity were less than 1 microgram equiv. of 14C-aminoglutethimide/g tissue. Metabolite profiles in urine, tissues and faeces showed extensive metabolism of the drug in a pattern similar to that found in the rat.     

Disposition of [14C]povidone after oral administration to the rat

The tissue distribution and excretion of 14C-labelled povidone (polyvinylpyrrolidone; K-30; average mol wt 40,000) was studied in male Sprague-Dawley rats given a single oral dose. The major pathway of elimination of radioactivity was in the faeces, in which 90.8% of the administered dose was recovered after 12 hr and 98.4% after 48 hr. Amounts of radioactivity in major tissues and in the blood were not significantly different from those in untreated controls. A minor amount of radioactivity, representing 0.04% of the administered dose, was detected in the urine after 6 hr. Dialysis studies of [14C]povidone suggested that the absorbed species was a low-molecular-weight (less than 3500) oligomer. It was concluded that an oral dose of [14C]povidone is not significantly absorbed in the rat.     

The pharmacokinetics of nitrendipine. I. Absorption, plasma concentrations, and excretion after single administration of [14C]nitrendipine to rats and dogs

[14C]nitrendipine (3-ethyl 5-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, Bay e 5009, Baypress, Bayotensin) was administered to rats and dogs (intravenously, orally, intraduodenally, 0.5-50 mg/kg) in order to investigate absorption, disposition, and excretion of parent compound and metabolites. The absorption of radioactivity following oral administration of [14C]nitrendipine was rapid and almost complete in both species. Maximum concentrations of total radioactivity in plasma were reached after 1.2 (rat) or 0.7 h (dog). The radioactivity was eliminated from plasma with terminal half-lives of 57 (rat) and 188 h (dog) during an observation period up to 10 and 9 days, respectively. Unchanged nitrendipine contributed to the AUC of total radioactivity only 8-9% after intravenous and 1-2% after oral administration. The bioavailability of nitrendipine after oral administration amounted to 12% in rats and 29% in dogs due to a strong first pass elimination process. About two thirds of the radioactivity administered were excreted via faeces, one third via urine. Distinct sex-differences in the excretion pattern could be found in rats but not in mice. They were attributed to well-known sex differences of the metabolic capacities in rat liver. In rats the radioactivity excreted via bile (about 75% of the dose) was subject to a marked entero-hepatic circulation, about 50% of the amount excreted being reabsorbed. The radioactive residues in the body were low (0.5% of the dose after 2 days in rats; less than or equal to 0.6% after 9 days in dogs).     

Metabolism of 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo [4,3-alpha] [1,4] benzodiazepine, triazolam, a new central depressant. I. Absorption, distribution and excretion in rats, dogs and monkeys.

1. Peak radioactivity in the blood was reached at 30 min after i.p. and 1 h after oral dosing of [14C]triazolam to rats. In dogs, peak blood level was observed at 30 min after oral dosing. 2. Daily dosing of triazolam to male rats for 21 days caused a gradual increase in blood level, with peak at 1 h after dosing. 3. The rate of binding of triazolam plus its metabolites to plasma protein of rats was about 30% at 15 min and 6 h. 4. In rats, the majority of the activity of the intra-intestinally administered [14C]triazolam was found in the small intestines in 6 h. 5. About 58% of the oral dose and 77% of the i.p. dose were recovered in the bile of rats in 48 h after dosing. When the bile from one rat was introduced into the duodenum of a second rat, approximately 37% was recovered in the bile of the second animal in 24 h. 6. In male rats, high radioactivity was seen in the liver, kidneys, adrenals and heart, and low in the CNS. By 96 h after dosing, radioactivity in the liver, blood and kidneys was very low, and was undetectable in other tissues and organs. Radioactivity levels in tissues after daily dosing for 7, 14 and 21 days did not differ appreciably from single administration. 7. In monkeys, activity was high in the liver, kidneys and skin following oral administration and low in the CNS. 8. After oral administration of [14C]triazolam to pregnant rats, the activity in the uterus and placenta was higher than that in the maternal blood. The activity in the foetus was low. 9. In rats given [14C]triazolam orally or i.p., 85% and 12% of the oral dose, and 82% and 14% of the i.p. dose were recovered in the faeces and urine, respectively, in 96 h. The rate of cumulative faecal and urinary excretion after repeated dosing was similar to the single dosing with 80% and 14% of the activity recovered, respectively, in faeces and urine in 6 days. In dogs, 50% of the oral dose was found in the faeces and 40% in the urine. 10. Radioactivity in the milk of rats was maximal at 4 h after oral dosing. It declined to 34% of the peak level 48 h later.     

Metabolism, excretion and distribution of the flame retardant tetrabromobisphenol-A in conventional and bile-duct cannulated rats

1. 14C-TBBP-A (2,2-bis(4-hydroxy-3,5-dibromophenyl)propane) was administered orally to the conventional and bile-duct cannulated male Sprague-Dawley rat (2.0 mg/kg body weight). Urine, bile and faeces were collected daily for 72 h, and selected tissues were removed for distribution studies. 2. Faeces was the major route of elimination of TBBP-A in the conventional rat (91.7% of dose), and urine was a minor elimination route (0.3%). Enterohepatic circulation was suggested by biliary excretion of 71.3% and faecal excretion of 26.7% of the administered radioactivity in the bile-duct cannulated rat. 3. 14C-labelled residues in tissues were 2% in the conventional rat, and < 1% in the bile-duct cannulated rat. The large and small intestines contained the majority of the tissue 14C activity for both groups of rat. Levels of TBBP-A in liver were < 0.1% and in fat were below the level of quantification. 4. Three metabolites were characterized in 0-24 h bile samples. Glucuronic acid and sulphate ester conjugates were characterized by mass spectrometry. More than 95% of the extractable faecal 14C was identified as parent TBBP-A. 5. Negligible amounts of TBBP-A-derived 14C were associated with carrier proteins in the urine and bile.     

Transdermal administration of radiolabelled [14C]rotigotine by a patch formulation: a mass balance trial

BACKGROUND AND OBJECTIVE: The dopamine agonist rotigotine has been formulated in a silicone-based transdermal system for once-daily administration. The objective of the present study was to characterise the mass balance of rotigotine in humans after administration of a single transdermal patch containing radiolabelled [(14)C]rotigotine and to quantify the pharmacokinetic profiles of total radioactivity and the corresponding rotigotine plasma concentrations. METHODS: In a phase I trial, six healthy male Caucasian subjects were administered a single 10 cm(2) patch containing 4.485mg of unlabelled and 0.015mg of [(14)C]-labelled rotigotine (total radioactivity 0.09 MBq per patch) with a patch-on period of 24 hours. Radioactivity was determined by liquid scintillation counting in unused patches, used patches, skin wash samples after 24 hours, plasma, urine and faeces samples up to 96 hours and skin stripping samples at 96 hours post-application. Unconjugated rotigotine in plasma samples was determined by liquid chromatography with tandem mass spectrometry. Plasma samples were taken predose and 2, 4, 6, 8, 12, 24, 48, 72 and 96 hours after patch application. RESULTS: The rotigotine transdermal patch was well tolerated, and all subjects completed the trial. A total of 94.6% of the administered dose was recovered within 96 hours after patch application inclusive of the residual amounts in the patch. Within 24 hours, 51% of the total radioactivity was delivered to the human body system and 46.1% was systemically absorbed. Total radioactivity recovered in urine and faeces was 30.4% and 10.2%, respectively, of the radioactivity applied (corresponding to 65.8% and 21.8% of the dose absorbed, respectively). CONCLUSIONS: The mass balance of rotigotine within 96 hours after transdermal delivery of rotigotine via a 10 cm(2) [(14)C]rotigotine patch with a total drug content of 4.5mg (corresponding to the nominal dose of 2mg/24 hours for the marketed rotigotine transdermal system) has been 95% explained. The systemic absorption was 46.1% of the administered dose, the majority of which was cleared from the body via urine and faeces within 96 hours after patch application.     

Percutaneous absorption of [14C]methacrylamide in animals

Percutaneous absorption of [^l4C]methacrylamide was determined in rabbits, rats and mice. Radioactivity in blood of rabbits increased rapidly after IV injection, after topical application with a cloth and after direct topical application of a 15 or 5% test solution, suggesting high permeability of the skin for methacrylamide. Radioactivity then began to decrease exponentially within 1 h. Tissue radioactivity 24 h after IV dosing was high in blood, liver and serum, and low in brain, nerve and muscle. The radioactivity was more uniformly distributed with the exception of liver, after application with a cloth and after direct contact than after IV dosing. When the application site was washed with water after direct application, decline of radioactivity in blood was accelerated slightly and a decrease in radioactivity in some tissues was found, although the difference between non-wash and wash groups was not significant in either the declining curve or the tissue radioactivity, with the exception of serum for the latter. Between 25 and 60% of the radioactivity found in tissues was protein-bound after 24 h. Recovery of radioactivity in urine was highest after IV administration, intermediate after direct contact, and lowest after cloth application. Radioactivity in expired air and bile was small. Both radioactivity in tissues and its recovery in urine in rats, and tissue radioactivity in mice, were lower than in rabbits, when adjusted for dose per unit body weight, suggesting lower skin permeability for methacrylamide in the former species. In rats, radioactivity in some tissues was significantly decreased after washing. An autoradiographic study on rabbit skin indicated that the test material penetrated the skin largely through hair follicles.     

Percutaneous absorption of the 21-β-benzoylamino iso-butyrate of triamcinolone acetonide by rats and rabbits

The percutaneous absorption of the β-benzoylaminoisobutyrate of [³H]-triamcinolone acetonide (TBI) has been studied in rats and rabbits. Up to about 5% and 20% of the applied dose was absorbed by rats and rabbits respectively during 5 days. In both species, absorption was mainly complete after about 3 days, although most of the dose was still present at the site of application. Of the absorbed radioactivity, the rat excreted about 1% and 2% of the dose respectively in the urine and faeces and the rabbit 9% and 4% respectively in 5 days. Peak plasma concentrations of drug equivalents occurred in rats at about 48 h (1.9 ng/ml) and in rabbits at about 72 h (2.6 ng/ml).     

Absorption and excretion of 1-amino-2-naphthol-6-sulphonic acid in rats and rabbits.

1-amino-2-naphthol-6-sulphonic acid (ANSA) and compounds of similar structure are metabolites formed by azo reduction in mammals from several commonly used food colours, e.g. Sunset Yellow FCF and Food Red 17. At our institute it has been shown that ANSA produces bile duct proliferation when given orally to rabbits. Furthermore Orange RN which by azo reduction yields ANSA (and aniline) induce the same effect in pigs (Olsen et al., 1973) but not in rats (Gaunt et al., 1971). Using 35S-labelled ANSA the absorption and excretion as well as the localisation in the liver cell of ANSA was investigated in rats and rabbits. The results after p.o. administration shows that the rabbit absorbs and excretes into the urine a significant larger amount of ANSA (30-40%) than the rat (6-13%). The results after i.v. administration shows that some 60% of the injected dose is excreted in the urine in both species. In the rat 15-20% are recovered from the faeces, while only traces (0.1-0.5%) are found in faeces of rabbits. A significant amount of ANSA was retained in the blood and the liver of both species 24 and 48 hours after administration. After differential centrifugation of liver homogenates the majority of ANSA was found in the 9000 x g supernatant.     

Metabolism,excretion and distribution of the flame retardant tetrabromobisphenol-A in conventional and bile-duct cannulated rats

1. ¹⁴C-TBBP-A (2,2-bis(4-hydroxy-3,5-dibromophenyl)propane) was administered orally to the conventional and bile-duct cannulated male Sprague-Dawley rat (2.0?mg/kg body weight). Urine, bile and faeces were collected daily for 72 h, and selected tissues were removed for distribution studies. 2. Faeces was the major route of elimination of TBBP-A in the conventional rat (9.7% of dose), and urine was a minor elimination route (0.3%). Enterohepatic circulation was suggested by biliary excretion of 71.3% and faecal excretion of 26.7% of the administered radioactivity in the bile-duct cannulated rat. 3. ¹⁴C-labelled residues in tissues were 2% in the conventional rat, and &;lt;1% in the bile-duct cannulated rat. The large and small intestines contained the majority of the tissue ¹⁴C activity for both groups of rat. Levels of TBBP-A in liver were &;lt; 0.1%, and in fat were below the level of quantification. 4. Three metabolites were characterized in 0-24 h bile samples. Glucuronic acid and sulphate ester conjugates were characterized by mass spectrometry. More than 95% of the extractable faecal ¹⁴C was identified as parent TBBP-A. 5. Negligible amounts of TBBP-A-derived ¹⁴C were associated with carrier proteins he urine and bile.     

Disposition and metabolism of double-labeled [3H and 14C] N-methyl-2-pyrrolidinone in the rat

The disposition of N-methyl-2-pyrrolidinone (NMP) was studied in the rat using tritium-labeled ([4-3H]NMP) and carbon-14-labeled ([methyl-14C]NMP and [ring-14C]NMP) radioisomers. Male Sprague-Dawley rats were administered a single intravenous dose (45 mg/kg) of 5.0 microCi of 3H or 14C for single-labeled disposition studies or 5.0 microCi of 3H and 2.5 microCi of 14C for double-labeled studies (2:1 ratio, 3H:14C). Plasma levels of intact NMP were analyzed by HPLC through 6 hr after dosing and suggested a rapid distribution phase followed by a slow elimination phase. The half-life for the terminal elimination phase from plasma was about 7 hr for both 14C-isomers and 9.9 hr for the 3H-isomer. The major route of excretion of radioactivity was via the urine and accounted for about 70% of the dose within 12 hr. After 24 hr, cumulative excretion in urine represented about 80% of the dose. The 2:1 ratio of administered 3H:14C was maintained in urine through 6 hr. Measurement of radioactivity in tissues at 6 hr showed the liver and intestines to contain the highest accumulations of radioactivity, representing approximately 2% and 3% of the dose, respectively. Tissue distribution of radioactivity was similar for all three radiolabeled isomers and showed that NMP was extensively distributed to all major organs. Radiomonitored HPLC analyses of urine revealed the presence of one major and two minor metabolites. The major metabolite, representing 70-75% of the administered dose of radioactivity, was found to retain all three radiolabeled positions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism,excretion and pharmacokinetics of [14C]glasdegib (PF-04449913) in healthy volunteers following oral administration

1.?The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100?mg/100 μCi [¹⁴C]glasdegib to six healthy male volunteers (NCT02110342).

2.?The peak concentrations of glasdegib (890.3?ng/mL) and total radioactivity (1043 ngEq/mL) occurred in plasma at 0.75?hours post-dose. The AUC_inf were 8469?ng.h/mL and 12,230 ngEq.h/mL respectively, for glasdegib and total radioactivity.

3.?Mean recovery of [¹⁴C]glasdegib-related radioactivity in excreta was 91% of the administered dose (49% in urine and 42% in feces). Glasdegib was the major circulating component accounting for 69% of the total radioactivity in plasma. An N-desmethyl metabolite and an N-glucuronide metabolite of glasdegib represented 8% and 7% of the circulating radioactivity, respectively. Glasdegib was the major excreted component in urine and feces, accounting for 17% and 20% of administered dose in the 0–120?hour pooled samples, respectively. Other metabolites with abundance <3% of the total circulating radioactivity or dose in plasma or excreta were hydroxyl metabolites, a desaturation metabolite, N-oxidation and O-glucuronide metabolites.

4.?Elimination of [¹⁴C]glasdegib-derived radioactivity was essentially complete, with similar contribution from urinary and fecal routes. Oxidative metabolism appears to play a significant role in the biotransformation of glasdegib.     

The absorption of [G-3H]-acetylglycyrrhetate after oral administration to rats.

A tritium-labelled form of aluminium acetylglycyrrhetate has been synthesised by catalytic exchange with tritiated water. An oral dose of aluminium [3H]-acetylglycyrrhetate to rats was mainly excreted in the faeces (a mean of 73%). A mean of 4% was excreted in the urine and after five days 17% of the radioactivity was retained in the carcass. The amounts of non-volatile (drug-related radioactivity excreted in faeces and urine during five days were 65% and 3%, respectively, while 6% was retained in the carcass. The total amount of tritiated water produced was 24% of the dose. Experiments in rats with cannulated bile ducts indicated that much of the faecal radioactivity represented unabsorbed drug. 15% of an oral dose was eliminated in bile during 2 days. A minimum value for the extent of absorption of an oral dose was estimated as 21%. Plasma levels of radioactivity were very low and peak levels of drug-related radioactivity were reached at 30 min and represented about 0.2% of the dose in total plasma.     

Metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline in the male rat

The metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was studied in the male rat using the radiochemical labels 14C and 3H at positions 2 and 5 of the molecule, respectively. Adult male Fischer 344 rats were administered [2-14C]IQ or [5-3H]IQ by oral gavage at dose levels of 20 or 40 mg/kg body weight. Rats were also given [2-14C]IQ in the diet at a dose level of 300 ppm for 2 days and after administration of unlabelled IQ (300 ppm) in the diet for approximately 6.5 wk for an additional 2 days. In the initial 48 hr following oral administration of 20 or 40 mg [2-14C]IQ/kg body weight, about 40-50% radioactivity was recovered in the urine, and about 30-38% radioactivity was recovered in the faeces. In the initial 72 hr following consumption of [2-14C]IQ (300 ppm) in the diet about 26% radioactivity was recovered in the urine and about 61% radioactivity was recovered in the faeces. Following cannulation of the bile ducts, rats administered a single dose of [2-14C]IQ (40 mg/kg body weight) by oral gavage excreted about 15% of the administered dose in the bile over a period of 2 days. Urine from rats given [2-14C]IQ contained three main polar metabolites that included a glucuronide, a sulphate ester and IQ sulphamate, and a number of less polar metabolites that included IQ, 2-acetylamino-3-methylimidazo[4,5-f]quinoline, 2-aminoimidazo[4,5-f]quinoline and 2-amino-3,6-dihydro-3-methyl-7H-imidazo[4,5-f]quinoline-7-one (7-OH-IQ). Administration of [2-14C]IQ by oral gavage or in the diet gave the same metabolites, but in different amounts. In the faeces of rats given [2-14C] by oral gavage, IQ-sulphamate was the major metabolite in the polar fraction. Non-polar metabolites similar to those found in the urine were also present, but in different amounts. A major, non-polar faecal metabolite, 7-OH-IQ was probably formed as a result of the activity of the intestinal bacterial flora. In rats given a single gavage dose of [2-14C]IQ, excretion of metabolites was higher in the urine and lower in the faeces compared with that in animals fed [2-14C]IQ in the diet. One polar metabolite present in the urine, IQ-sulphamate (39%), was found at considerably higher levels in rats dosed orally with IQ compared with those fed IQ (less than 6%). Thus, IQ is extensively metabolized to give a number of polar and non-polar metabolites, the amounts of which depend, in part, on the mode of dosing.