Urinary and biliary metabolites of mephentermine in male Wistar rats

1. Excretion of urinary and biliary radioactivity, and metabolites of [3H]mephentermine (MP), after i.p. or subcutaneous administration of [3H]MP to male Wistar rats, were determined by preparative t.l.c.-liquid scintillation counting. 2. About 45% of the radioactivity administered i.p. was excreted in the 24 h urine. The major urinary metabolite was conjugated p-hydroxymephentermine (p-hydroxy-MP), which accounted for about 18% of the administered radioactivity in the 24 h urine. 3. About 4.2% of the radioactivity administered subcutaneously was excreted in bile during 24 h. The major biliary metabolite was conjugated p-hydroxy-MP, which accounted for about 39% of the radioactivity excreted in the bile in 24 h. 4. Urinary and biliary minor metabolites detected were phentermine (Ph), p-hydroxyphentermine (p-hydroxy-Ph), N-hydroxyphentermine (N-hydroxy-Ph), N-hydroxymephentermine (N-hydroxy-MP) and their conjugates, and conjugated MP. 5. The conjugates were considered to be glucuronides from the inhibitory effect of saccharic acid 1,4-lactone on their hydrolysis with beta-glucuronidase. 6. Biliary excretion rates of conjugated p-hydroxy-Ph and p-hydroxy-MP reached maxima at 3 to 4 h, and non-conjugated metabolites were maximal at 1 to 2 h, after administration. 50% of the biliary metabolites was excreted within 5 h.     

Identification of the metabolites of irinotecan, a new derivative of camptothecin, in rat bile and its biliary excretion.

1. To investigate the metabolites and biliary excretion of new camptothecin analogue, irinotecan, the drug was administered i.v. to rats (10 mg/kg) and bile, urine and faeces were collected. 2. In rat bile, unchanged irinotecan, the metabolite 7-ethyl-10-hydroxycamptothecin (EHCPT) and unknown metabolite M-1 were found by t.l.c. and h.p.l.c. From beta-glucuronidase hydrolysis, n.m.r. spectrometry and mass spectrometry, M-1 was identified as EHCPT-glucuronide (EHCPT Glu). Other metabolites in the bile were negligible. 3. The cumulative biliary and urinary excretion of radioactivity after dosage of rats with irinotecan were 62.2% and 33.3% dose, respectively, and 9.0% of the radioactivity was excreted in the faeces. 4. Approx. 55% of the biliary radioactivity excreted in 24 h was unchanged irinotecan, 22% was EHCPT Glu, and 9% was EHCPT. 5. Approx. 18% of the biliary radioactivity was reabsorbed from the intestine.     

Identification of the metabolites of irinotecan,a new derivative of camptothecin,in rat bile and its biliary excretion

1. To investigate the metabolites and biliary excretion of new camptothecin analogue, irinotecan, the drug was administered i.v. to rats (10?mg/kg) and bile, urine and faeces were collected.

2. In rat bile, unchanged irinotecan, the metabolite 7-ethyl-10-hydroxycamptothecin (EHCPT) and unknown metabolite M-1 were found by t.l.c. and?h.p.l.c. From β-glucuronidase hydrolysis, n.m.r. spectrometry and mass spectrometry, M-1 was identified as EHCPT-glucuronide (EHCPT Glu). Other metabolites in the bile were negligible.

3. The cumulative biliary and urinary excretion of radioactivity after dosage of rats with irinotecan were 62.2% and 33.3% dose, respectively, and 9.0% of the radioactivity was excreted in the faeces.

4. Approx. 55% of the biliary radioactivity excreted in 24?h was unchanged irinotecan, 22% was EHCPT Glu, and 9% was EHCPT.

5. Approx. 18% of the biliary radioactivity was reabsorbed from the intestine.     

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).     

Effects of inducers and inhibitors of mixed-function oxidases on the biliary excretion of pentacaine metabolites

The biliary excretion of 3H-pentacaine and its metabolites was studied in rats pretreated with an inducer or inhibitor of mixed-function oxidases. Over one-fourth (25.8 per cent) of a 2 mg kg-1 intraportal dose of 3H-pentacaine was excreted in bile in urethaneanaesthetized control rats within 3 h. The radioactivity appeared in the form of the parent drug, basic metabolites, and metabolite conjugates, 3.1, 86.5, and 10.4 per cent of the total radioactivity excreted, respectively. Pretreatment of rats with phenobarbital enhanced only slightly the biliary excretion of basic metabolites, and pretreatment with 3-methylcholanthrene had no effect. Phenobarbital also increased the initial rate of excretion of conjugates, but this effect was not sustained. 3-Methylcholanthrene had a tendency to impair excretion of conjugates by bile. Pretreatment of rats with SKF 525-A decreased the biliary excretion of both basic metabolites and conjugates while cimetidine did not alter significantly the biliary excretion of pentacaine metabolites. These results suggest that the canalicular transport of metabolites may be the most important factor in controlling pentacaine metabolite excretion in bile.     

Kinetics of [3H]trifluoperazine in bile fistula rats.

1. Anaesthetized male rats with a bile fistula received 12-3 micron mol/kg [9-3H]tri-fluoperazine into the tail vein, and the biliary excretion of total radioactivity, unchanged drug and phenolic glucuronides was followed for 8 h. 2. About half of the administered radioactivity apeared in bile within 8 h;80% of the biliary metabolites were unextractable even after beta-glucuronidasearylsulphatase hydrolysis; about 10% were glucuronides of 7-hydroxytrifluoperazine and its N-demethylated analogue; approx. 0-6% of the excreted radioactivity was unchanged drug. 3. A more rapid excretion, but a similar metabolite pattern, was observed when the drug was administered into the portal vein and bile was collected for 2 h. 4. Rats pre-treated with trifluoperazine per os for 3 weeks and then given the radioactive dose into the tail vein excreted increased quantities of the demethylated phenol glucuronide, while the other metabolities remained unchanged.     

Studies of the metabolism and excretion of silybin in the rat]

The metabolism and excretion of silybin (as N-methyl-glucamine salt) was investigated after intravenous and oral administration to rats. In the urine, silybin was excreted mostly in the unchanged form after intravenous as well as oral application, whilst in the bile it appeared above all in the form of metabolites. By hydrolysis with arylsulfatase/beta-glucuronidase, the metabolites were identified as sulfate and glucuronide conjugates of silybin and dehyrosilybin; the latter appeared in small quantities as a dehydrated product of silybin. After intravenous injection of 20 mg silybin per kg body weight, the excreted amount of silybin after 48 h was 8%, whereas 76% was eliminated in the bile within the same period of time. After oral application of 2--20 mg silybin/kg body weight 20% after 40 mg/kg 35% and after 120 mg/kg 20% of the administered silybin was excreted in the bile during 48 h. The maximum excretion rate was achieved at application of 20 mg/kg p.o. after 1 h. At this dosage, 2--5% was eliminated within the same time in the urine. The excretion of silybin mainly took place (more than 80% of the total of excreted bilybin) in the bile, both after oral and intravenous administration.     

Sex differences in the metabolism and excretion of nilvadipine, a new dihydropyridine calcium antagonist, in rats

1. The metabolic profiles of nilvadipine in the urine and bile of male and female rats were studied after i.v. dosing with 1 mg/kg of the 14C-labelled compound. 2. Excretion rates of the dosed radioactivity in male and female rats, respectively, in the first 48 h were 84.1% and 59.1% in bile, 12.0% and 36.9% in urine, and 2.5% and 3.6% in faeces. 3. Comparison of biliary and urinary excretion for each radioactive metabolite after dosing with 14C-nilvadipine, showed marked sex-related differences in the excretion routes of several metabolites. In male rats, metabolite M3, having a free 3-carboxyl group on the pyridine ring, was not excreted in urine, but in female rats urinary excretion of M3 accounted for 4.7% of the dose. One reason for the lower urinary excretion of radioactivity by males than by females was that the main metabolite, M3, was not excreted in the urine of the male rats. 4. To clarify the sex difference in the route of excretion of M3, this metabolite (M3) was given i.v. to rats. No excretion of the metabolite was observed in urine of male rats within 24 h but, in marked contrast, 41.5% of the dose was excreted in urine of females in the same period.     

Metabolism of peruvoside in man

Summary The metabolism of tritiated peruvoside was investigated in 4 subjects, one of whom had a biliary fistula. The serum half life of radioactivity and urinary, fecal and biliary excretion were measured. Similar amounts of radioactivity were excreted in urine after oral and intravenous administration. The total excretion in 48 h was similar in all subjects (32.9% to 37.1% of dose administered). No unchanged drug was detected in the urine by GLC/MS/MID. Two metabolites, A and B, appeared in the excreta, B being cardio-inactive. Although large amounts of radioactivity were excreted in bile, no evidence was found of enterohepatic recirculation of the drugSupported by Deutsche Forschungsgemeinschaft     

Disposition and metabolism of 2-(2'(1',3'-dioxolan-2-yl)-2- methyl-4-(2'-oxopyrrolidin-1-Yl)-6-nitro-2h-1-benzopyran (SKP-450) in rats.

The disposition and metabolism of the new antihypertensive agent 2-(2"(1", 3"-dioxolan-2-yl)-2-methyl-4-(2'-oxopyrrolidin-1-yl)-6-nitro -2H-1-benzopyran (SKP-450) were investigated in male rats after single oral and i.v. doses of 14C-labeled compound. After an oral 2.0 mg/kg dose, mean radiocarbon recovery was 98.2 +/- 2.3% with 31.1 +/- 7.3% in the feces and 67.1 +/- 14.3% in the urine. Biliary excretion of radioactivity for the first 24-h period was approximately 40%, suggesting that SKP-450 is cleared either by hepatobiliary excretion or by renal excretion. SKP-450 was well absorbed; bioavailability calculated on the basis of radioactivity was 68 to 97%. Tissue distribution of the radioactivity was widespread with high concentrations in the liver and kidney but low central nervous system penetration. Radio-HPLC analysis of bile and urine from rats indicated the extensive metabolism of SKP-450 into oxidative metabolites. Oxidative metabolism of the dioxolanyl ring resulted in an aldehyde intermediate, subsequently confirmed in vitro, which was further oxidized to the corresponding carboxylic acid (M1) or reduced to the corresponding alcohol (M3). No parent drug was detected in the urine or bile. Glucuronide conjugate of M3 was also detected in urine and bile, accounting for 5.8 +/- 2.1 and 8.9 +/- 3. 7% of the excreted radioactivity, respectively. Quantitative data obtained from plasma samples suggest that the majority of circulating radioactivity was associated with metabolites. Our results suggest that the long duration of pharmacological activity of SKP-450 (>10 h) is largely attributable to its metabolites.     

Species differences in disposition of benzo[a]pyrene

Comparison of disposition of benzo[a]pyrene (B[a]P) among Sprague-Dawley rats, Gunn rats, hamsters, and guinea pigs was performed. [3H]B[a]P was administered intratracheally to animals, and the rate of excretion of radioactivity into bile, types of metabolites of B[a]P in bile, and distribution of radioactivity among tissues were determined. In Sprague-Dawley rats, Gunn rats, and guinea pigs, the rate of excretion of radioactivity was dependent upon the administered dose. Excretion and tissue distribution of radioactivity were qualitatively similar among these species although quantitative differences were observed. In hamsters, the rate of excretion was essentially independent of dose at the concentrations examined (0.16 and 350 micrograms). The major difference between hamsters and the other species was that increased amounts of radioactivity were retained in lungs of hamsters at the lower dose with a proportional decrease in the amount of radioactivity excreted into bile. The types and relative amounts of conjugated and nonconjugated metabolites of B[a]P were similar in bile of Sprague-Dawley rats and hamsters. Smaller amounts of glucuronides and larger amounts of sulfate conjugates were detected in bile of Gunn rats than in bile of Sprague-Dawley rats or hamsters. Metabolites in bile of guinea pigs were markedly different from those in the other species in that approximately 90% of the metabolites were thioether conjugates. Buthionine sulfoxime was used to reduce tissue levels of glutathione in Sprague-Dawley rats. When liver and lung glutathione levels were reduced to 30% and 82% of control levels, respectively, the amount of radioactivity excreted into bile was not significantly different from controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fate and distribution of 3H-labeled T-2 mycotoxin in guinea pigs

T-2 toxin is a potent cytotoxic metabolite produced by the Fusarium species. The fate and distribution of 3H-labeled T-2 toxin were examined in male guinea pigs. Radioactivity was detected in all body tissues within 30 min after an im injection of an LD50 dose (1.04 mg/kg) of T-2 toxin. The plasma concentration of trichothecene molar equivalents versus time was multiphasic, with an initial absorption half-life equal to or less than 30 min. Bile contained a large amount of radioactivity which was identified as HT-2, 4-deacetylneosolaniol, 3'-hydroxy HT-2, 3'-hydroxy T-2 triol, and several more-polar unknowns. These T-2 metabolites are excreted from liver via bile into the intestine. Within 5 days, 75% of the total radioactivity was excreted in urine and feces at a ratio of 4 to 1. The appearance of radioactivity in the excreta was biphasic. Metabolic derivatives of T-2 excreted in urine were T-2 tetraol, 4-deacetylneosolaniol, 3'-hydroxy HT-2, and several unknowns. These studies showed a rapid appearance in and subsequent loss of radioactivity from tissues and body fluids. Only 0.01% of the total administered radioactivity was still detectable in tissues at 28 days. The distribution patterns and excretion rates suggest that liver and kidney are the principal organs of detoxication and excretion of T-2 toxin and its metabolites.     

Metabolism and excretion of CP-122,721, a non-peptide antagonist of the neurokinin NK1 receptor, in dogs: identification of the novel cleaved product 5-trifluoromethoxy salicylic acid in plasma

The metabolism and excretion of a potent and selective substance P receptor antagonist, CP-122,721, have been studied in beagle dogs following oral administration of a single 5 mg kg(-1) dose of [(14)C]CP-122,721. Total recovery of the administered dose was on average 89% for male dogs and 95% for female dogs. Approximately 94% of the radioactivity recovered in urine and feces was excreted in the first 72 h. Male bile duct-cannulated dogs excreted a mean of approximately 56% of the dose in bile, approximately 11% in feces, and approximately 25% in urine. The sum of radioactivity in bile and urine indicates >80% of the [(14)C]CP-122,721-derived radioactivity was absorbed by the gastrointestinal tract. CP-122,721 was extensively metabolized in dogs, and only a small amount of parent CP-122,721 was excreted as unchanged drug. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or feces. The major metabolic pathways of CP-122,721 were O-demethylation, aromatic hydroxylation, and indirect glucuronidation. The minor metabolic pathways included: Aliphatic oxidation at the piperidine moiety, O-dealkylation of the trifluoromethoxy group, and N-dealkylation with subsequent sulfation and/or oxidative deamination. In addition, the novel cleaved product 5-trifluoromethoxy salicylic acid (TFMSA) was identified in plasma. These results suggest that dog is the most relevant animal species in which the metabolism of CP-122,721 can be studied for extrapolating the results to humans.     

The excretion of 3H-papaverine in the rat

The excretion of ³H-papaverine has been studied in the rat. After per oral as well as parenteral administration about 85 per cent of the administered radioactivity is excreted in faeces and urine in 4 days, and only negligible amounts of this radioactivity consist of unchanged ³H-papaverine; most of the radioactivity is recovered in the faeces in the first 24 hr.After an intravenous dose of ³H-papaverine, about 70 per cent of the tritium is excreted in the bile in 6 hr. All this radioactivity is due to conjugated metabolites, which after hydrolysis with glusulase, give five peaks on thin layer chromatograms. After intraduodenal administration of these conjugated metabolites, a very small absorption occurs, while after administration of the hydrolysed metabolites about 60 per cent of the dose is excreted in the bile. After intramuscular injection of ³H-papaverine radioactivity in the intestine follows quite good the time pattern of excretion of tritium in the bile. No significant difference was observed between control and bile cannulated rats with regard to the blood levels of radioactivity and ³H-papaverine. These results suggest that the bile is the main route of excretion of papaverine metabolites and that enterohepatic circulation of these metabolites is not important.     

Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat

The metabolism and disposition of tri-p-cresyl phosphate (TPCP) were studied in the rat after a single oral administration of [methyl-14C] TPCP. At a dosage of 7.8 mg/kg, most of the administered radioactivity was excreted in the urine (41%) and feces (44%) in 7 days. For 3 days, the expiratory excretion as 14CO2 amounted to 18% of the radioactivity, but was reduced to 3% by treatment of the animal with neomycin. In separate rats, the biliary excretion amounted to 28% of the dose in 24 hr. At a dose of 89.6 mg/kg, the radioactivity was excreted in urine (12%) and feces (77%) in 7 days, and the expired air (6%) in 3 days. At 24, 72, and 168 hr after oral administration, the concentration of radioactivity was relatively high in adipose tissue, liver, and kidney. The major urinary metabolites were p-hydroxybenzoic acid, di-p-cresyl phosphate (DCP), and p-cresyl p-carboxyphenyl phosphate (1coDCP). The biliary metabolites were DCP, 1coDCP, and the oxidized triesters, di-p-cresyl p-carboxyphenyl phosphate (1coTPCP), and p-cresyl di-p-carboxyphenyl phosphate (2coTPCP). The main fecal metabolite was TPCP, and the others were similar to those of bile. Following oral administration, TPCP was absorbed from the intestine, distributed to the fatty tissues, and moderately metabolized to a variety of products of oxidation and dearylation of TPCP, which were then excreted in the urine, feces, bile, and expired air. The intestinal microflora appeared to play an important role in degrading biliary metabolites to 14CO2 through the enterohepatic circulation in rats.     

Sex differences in the metabolism and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats

1. The metabolic profiles of nilvadipine in the urine and bile of male and female rats were studied after i.v. dosing with 1?mg/kg of the ¹⁴C-labelled compound.

2. Excretion rates of the dosed radioactivity in male and female rats, respectively, in the first 48?h were 8.41% and 59.1% in bile, 12.0% and 36.9% in urine, and 2.5% and 3.6% in faeces.

3. Comparison of biliary and urinary excretion for each radioactive metabolite after dosing with ¹⁴C-nilvadipine, showed marked sex-related differences in the excretion routes of several metabolites. In male rats, metabolite M3, having a free 3-carboxyl group on the pyridine ring, was not excreted in urine, but in female rats urinary excretion of M3 accounted for 4.7% of the dose. One reason for the lower urinary excretion of radioactivity by males than by females was that the main metabolite, M3, was not excreted in the urine of the male rats.

4. To clarify the sex difference in the route of excretion of M3, this metabolite (M3) was given i.v. to rats. No excretion of the metabolite was observed in urine of male rats within 24?h but, in marked contrast, 41.5% of the dose was excreted in urine of females in the same period.     

Effect of diphenylhydantoin on the biotransformation and biliary excretion of imipramine in rats.

1. Rats with biliary fistula excrete 18% of an intraperitoneal dose of [14C]imipramine (80 mg/kg) in bile within 2-5 h. Diphenylhydantoin (46 mg/kg) simultaneously administered intravenously decreases the biliary excretion of imipramine plus metabolites to 7% dose. With or without diphenylhydantoin, the highest biliary concentration of imipramine plus metabolites occurs 30-60 min after dosage. 2. With or without administration of diphenylhydantoin, 83% of the bile radioactivity is present as the conjugated 2-hydroxylated metabolites of imipramine. With imipramine alone, more conjugated 2-hydroxydesmethyl-imipramine than conjugated 2-hydroxyimipramine is excreted in the bile. Diphenylhydantoin reverses this order. 3. Administration of diphenylhydantoin does not significantly alter the concentration of imipramine plus metabolites in plasma, liver, lung and brain measured at five consecutive 30 min periods after dosage.     

Excretion of [3H]triptolide and its metabolites in rats after oral administration

Aim： To investigate the routes of elimination and excretion for triptolide recovered in rats.
Methods： After a single oral administration of [3H]triptolide （0.8 mg/kg, 100 μCi/kg） in Sprague Dawley rats, urine and fecal samples were collected for 168 h. To study biliary excretion, bile samples were collected for 24 h through bile duct cannulation. Radioactivity was measured using a liquid scintillation analyzer, and excretion pathway analysis was performed using an HPLC/on-line radioactivity detector.

Results： The total radioactivity recovered from the urine and feces of rats without bile duct ligation ranged from 86.6%–89.1%. Most of the radioactivity （68.6%–72.0%） was recovered in the feces within 72 h after oral administration, while the radioactivity recovered in the urine and bile was 17.1%–18.0% and 39.0%–39.4%, respectively. The HPLC/on-line radiochromatographic analysis revealed that most of the drug-related radioactivity was in the form of metabolites. In addition, significant gender differences in the quantity of these metabolites were found： monohydroxytriptolide sulfates were the major metabolites detected in the urine, feces, and bile of female rats, while only traces of these metabolites were found in male rats.

Conclusion： Radiolabeled triptolide is mainly secreted in bile and eliminated in feces. The absorbed radioactivity is primarily eliminated in the form of metabolites, and significant gender differences are observed in the quantity of recovered metabolites, which are likely caused by the gender-specific expression of sulfotransferases.     

Characterization of metabolites of benz(j)aceanthrylene in faeces,urine and bile from rat

1. The excretion of benz[j]aceanthrylene (B[j]A) and the biotransformation products found in faeces, urine and bile of rat exposed to [³H]-labelled B[j]A have been studied. 2. About 95% of the administered radioactivity was excreted within 7 days, 79% via faeces and 16% via urine, and most of the radioactivity in urine and faeces was excreted within 2 days. 3. The B[j]A metabolites excreted between days 1 and 2, including those excreted in bile during the first 5.5 h in a separate experiment, were further characterized by HPLC, UV and electrospray/atmospheric pressure chemical ionization mass spectrometry. 4. In faeces, bile and urine, hydroxylated B[j]A metabolites predominated. The major metabolites in faeces were B[j]A-1,2-dihydrodiol-8-hydroxy and B[j]A-1,2-dihydrodiol-10-hydroxy. These metabolites were found as conjugated metabolites in the bile. The glucuronide conjugate of B[j]A-1,2-dihydrodiol-10-hydroxy was also a major metabolite in urine. Two sulphate conjugates of oxidized B[j]A were detected in bile, a sulphate conjugate of a B[j]A-dihydrodiol-phenol and B[j]A-1,2-dihydrodiol-10-sulphate. Trans B[j]A-1,2-dihydrodiol was detected in urine, faeces and bile. 5. These findings support the hypothesis that epoxidation at the cyclopenta ring is an important biotransformation pathway for B[j]A in vivo. In addition to the characterized metabolites, a large fraction of polar compounds, possibly glutathione conjugates, was also excreted in urine and bile.     

Assessment of enterohepatic circulation of radioactivity following a single dose of [14C]nimodipine in the rat

4 male Sprague-Dawley rats with bile-duct fistulae were joined in a cascade. The first animal was given 5 mg/kg of [14C]-labelled nimodipine administered intraduodenally as a bolus. The bile of animals 1 and 2 was dynamically infused intraduodenally respectively into animals 2 and 3 and the bile of animal 3 was collected in fractions and infused i.d. into animal 4. The excretion and the course of the plasma concentration were studied radiometrically. The described investigation technique allows a detailed determination of the quantity and the kinetics of reabsorption and excretion during each observed pass of radioactivity in the enterohepatic circulation. On the basis of the balance between radioactivity administered and recovered and of the course of the plasma concentration it has been shown, on the example of nimodipine, that the experiment successfully simulates the situation in the intact animal. The [14C]Nimodipine radioactivity is subject to pronounced enterohepatic circulation: on average 43% of the amount excreted with the bile is reabsorbed with each recirculation and 57% is excreted with the faeces, 81% and 19% of the quantity reabsorbed being excreted respectively with the bile and urine. Because of the repeated reabsorption, the effective dose is increased by 54% and the drop in plasma concentration is slowed down in the middle time interval between 3 and 15 h after administration. The kinetic processes (absorption, excretion) become slower with each recirculation. An increasing fraction of the absorbed radioactivity undergoes direct hepatic excretion, by-passing the systemic circulation.