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 Disposition and Metabolism of Amodiaquine in Small Mammals

1. 7-Chloro-4-(3′-diethylamino-4′-hydroxyanilino)quinoline (amodiaquine) labelled with ¹⁴C has been synthesized and administered in single doses to rats including bile-duct-cannulated rats, to guinea-pigs and to mice, by oral or parenteral routes.

2. Amodiaquine was extensively and rapidly absorbed from the rat intestinal tract. Excretion of total radioactivity from rats and guinea pigs was slow and prolonged and was <50% dose in 9 days. Excretion of ¹⁴C was predominantly in faeces of rats after oral and i.p. dosage, and guinea-pigs after i.p. dosage. Radioactivity in rat and guinea-pig urine was <11% dose.

3. Biliary excretion of ¹⁴C following oral or i.v. dosage to rats was 21% dose in 24?h.

4. Amodiaquine was extensively metabolized and conjugated with <10% dose excreted unchanged in urine or bile. Two major basic metabolites in rat urine were tentatively identified as the mono- and bis-desethyl amines.

5. 7-Chloro-4-(4′-diethyl-1′-methylbutylamino)quinoline (chloroquine) was excreted largely unchanged in urine of rats after oral or parenteral administration of single doses, with <5% dose excreted in rat bile in 24?h.     

Disposition of the plant phenol ellagic acid in the mouse following oral administration by gavage

1. The absorption, distribution and elimination of ³H-ellagic acid, a putative antimutagen and anticarcinogen, was studied in male Swiss-Webster mice following oral administration.

2. Levels of ³H-ellagic acid were highest in blood 30 min after administration, in urine and bile 120 min post-administration, and in liver, lung and kidney 15 min after administration.

3. Free ellagic acid and its conjugates were present in urine, bile and blood. H.p.l.c. analysis of the organic solvent extracts of urine, bile and blood indicated the presence of four metabolites in urine, two in blood and one in bile.

4. Sulphate ester, glucuronide and glutathione conjugates of ellagic acid were present in urine, bile and blood. H.p.l.c. analysis of organic solvent extracts after aryl sulphatase or β-glucuronidase treatment showed that ellagic acid was the major component present.

5. Absorption of ³H-ellagic acid occurred mostly within two hours after oral administration. Levels in blood, bile and tissues were low and almost all of the absorbed dose was excreted in urine.

6. More than 53% of the orally administered ³H-ellagic acid remained in the gastrointestinal tract at 24 h. Approximately 19% was excreted in faeces and 22% in urine at 24 h.

7. Of the 24 h faecal radioactivity 93% was extractable into organic solvents and more than 80% of this fraction was free ellagic acid. Only one metabolite was found in faeces.     

Studies on the absorption, distribution and elimination of 6-o-chlorophenyl-2,4-dihydro-2(N-methyl-piperazin-1-yl)-methylene-8-nitro-1H-imidazo[1,2-a] [1,4]benzodiazepin-1-one methanesulphonate in the male rat and rabbit.

The fate of a novel imidazo-benzodiazepine (I) was studied in male rats and rabbits using 14C and 3H-labelled I. In both species the compound was rapidly and widely absorbed after an oral dose of 5 mg/kg to give peak tissue and plasma levels after 1 hour in the rat and 4 hours in the rabbit. The highest concentrations of radioactivity were present in the liver (rat) and liver, kidney and subcutaneous fat (rabbit). Plasma levels of radioactivity fell to 3% of the maximum value in 24 hours in the rat but 48 hours were required for a similar fall in the rabbit. The main route of elimination of radioactivity was via the bile followed by excretion in the faeces. For the rat the rate of biliary elimination was 16.6% of the administered dose/hour; for the rabbit this rate was 5.6%/hour. Recovery of administered radioactivity during 0-24 hours for urine and faeces respectively was 4.8% and 69% for the rat and 23.2% and 10.9% for the rabbit. Up to 97% of the radioactivity administered to rats could be recovered in the excreta in the 7 days following dosing. Up to 90% of the dose administered to rabbits appeared in the excreta during 10 days. No unchanged (I) could be detected in the urine or bile. The radioactive metabolites were polar products, some of which were in the form of glucuronide conjugates.     

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the distribution and biliary excretion of polychlorinated biphenyls in rats.

Plasma disappearance, biliary excretion, and tissue distribution of two polychlorinated biphenyls (PCBs), 2,5,2′,5′-[³H]tetrachlorobiphenyl (4-CB) and 2,4,5,2′,4′,5′-[³H]hexachlorobiphenyl (6-CB), was determined in rats 10 days after oral administration of a single 10 or 25 μg/kg dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Plasma disappearance of both PCBs was not altered by TCDD treatment, but biliary excretion was depressed. Associated with the depressed excretion was a reduction in bile flow and concentration of 4-CB- and 6-CB-derived ³H in bile. Treatment with TCDD resulted in less PCB being distributed to the skin and a greater percentage of the dose being accumulated in the liver. The content of PCB-derived ³H in skeletal muscle, adipose tissue, and urine was similar in control and TCDD-treated rats. Extraction of bile with hexane showed that the majority of biliary radioactivity was in the form of polar metabolites and that the proportion of parent PCB (hexane-extractable radioactivity) to polar metabolites was not altered by TCDD treatment. In rats given 4-CB and sacrificed 1 hr later, the majority of radioactivity in the liver was hexane extractable, and the smaller amount of hepatic radioactivity due to polar 4-CB metabolites was greater in the TCDD treatment group than in the control group. When biliary metabolites of 4-CB were administered, biliary excretion of the metabolites was depressed in TCDD-treated animals. Thus, TCDD treatment impairs the initial and main excretory pathway for PCB elimination in the rat—biliary excretion—and alters the distribution of PCBs to the skin and liver.     

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.     

Comparative Studies on the Metabolic Disposition of 8-Chloro-6-pheny1–4H-s-triazolo[4,3-a][1,4]benzo-diazepine (D-40TA) and Nitrazepam after Single and Repeated Administration in Rats

Abstract

1. Orally administered D-40TA was absorbed by rats with a maximum blood level at 30 min and a half-life of 60 min. The blood level of orally administered nitrazepam reached a plateau which persisted for 90 min and then declined with a half-life of 90 min.

2. Both D-40TA and nitrazepam crossed the blood-brain barrier of rats. The 1-oxo metabolite of D-40TA is pharmacologically active, and also readily entered the brain.

3. Orally administered D-40TA and nitrazepam were eliminated in urine and faeces over 3 days, the larger part in faeces. In both cases, about 90% of the dose of radioactivity was eliminated from the body during the first 2 days after administration.

4. After intravenous injection of either [¹⁴C]D-40TA or [¹⁴C]nitrazepam, the radioactivity was excreted in bile at the same rate, 69 and 64% of the dose being recovered from the 24 h-bile, respectively. The biliary metabolites of both benzodiazepines underwent entero-hepatic cycling.

5. After daily oral administration of [¹⁴C]D-40TA or [¹⁴C]nitrazepam, the cumulative excretion closely paralleled the dosage of radioactivity. For both drugs, excretion was complete within 3 days of discontinuing medication. During repeated administrations of the labelled drugs, no increase in concn. of blood radioactivity 1 h after dosing was observed. With [¹⁴C]D-40TA-treated rats, most of the radioactivity still in the body 24 h after administration was recovered from the gastro-intestinal contents; only small amounts were in tissues. Dosing of [¹⁴C]D-40TA for 7 days caused no increase in tissue levels of radioactivity, except in the liver, where the radioactivity increased to about twice the level noted after a single administration.     

Studies on the Metabolism of d-Limonene (p-Mentha-1,8-diene): I. The Absorption,Distribution and Excretion of d-Limonene in Rats

Abstract

1. The absorption, distribution and excretion of d-limonene were investigated in rats using the ¹⁴C-labelled compound.

2. The highest concentration of radioactivity in blood was obtained 2 h after oral administration of [¹⁴C]d-limonene and most occurred in the serum fraction. Radioactivity in the tissues reached maximum 1 or 2 h after administration. Radioactivity in liver, kidney and blood was higher than in other tissues, but was negligible 48 h after administration. An autoradiographic study confirmed these findings of tissue distribution.

3. About 60% of administered radioactivity was recovered from urine, 5% from faeces and 2% from expired CO₂ within 48 h. In bile duct cannulated rats, about 25% of the dose was excreted in bile within 24 h.     

Intestinal absorption, intestinal distribution, and excretion of (14C) labelled hyoscine N-butylbromide (butylscopolamine) in the rat

Butylscopolamine was labelled with ¹⁴C and its gastrointestinal absorption, biliary and urinary excretion, enterohepatic circulation and gastrointestinal distribution were examined in anaesthetized rats. Biliary excretion was the main elimination route of intra-portally administered [¹⁴C]butylscopolamine, with 42% of the dose recovered in the bile during 12 h. About 6% of the radioactivity administered orally as [¹⁴C]butylscopolamine was excreted in the bile and 1.2 % in the urine during 24 h, which indicates poor gastrointestinal absorption of butylscopolamine in the rat. When collected radioactive bile was readministered intrajejunally, only about 7% of the radioactivity was recovered in bile and urine during 12 h, which suggests that only a small fraction of butylscopolamine and its metabolites engage in an enterohepatic circulation. After oral administration of [¹⁴C]butylscopolamine, radioactivity was found to accumulate in the wall of the distal small intestine, and about 20% of the dose was found in this tissue 24 h after drug administration. As a result, local anti-acetylcholine effects of butylscopolamine might be expected.     

Absorption,distribution, metabolism and excretion of telmesteine,amucolitic agent,in rat

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of ¹⁴C-telmesteine in the Sprague–Dawley rat.

2. ¹⁴C-telmesteine was rapidly absorbed after oral dosing (20 and 50mg kg^-1) with an oral bioavailability of > 90% both in male and female rats. The C_max and area under the curve of the radioactivity in plasma increased proportionally to the administered dose and those values in female rats were 30% higher than in male rats.

3. Telmesteine was distributed over all organs except for brain and the tissue/plasma ratio of the radioactivity 30min after dosing was relatively low with a range of 0.1–0.8 except for excretory organs.

4. Excretion of the radioactivity was 86% of the dose in the urine and 0.6% in the faeces up to 7 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 3% for the first 24 h. The unchanged compound mainly accounted for the radioactivity in the urine and plasma.

5. Telmesteine was hardly metabolized in microsomal incubations. A glucuronide conjugate was detected in the urine and bile, but the amount of glucuronide was less than 6% of excreted radioactivity.     

葛根有效成分的代谢研究——Ⅱ.14C-黄豆甙元在大鼠体内的吸收、分布和消除

本文采用纸片液体闪烁计数法研究了¹⁴C-黄豆甙元在大鼠体内的吸收、分布和消除。大鼠口服¹⁴C-黄豆甙元30分钟,血液即可测出放射性,6～8小时达高峰,以后缓慢下降。口服给药吸收不完全,由实验推论约有64.6%放射性可被吸收。静脉注射后,血放射性消失曲线分为快、慢两个时相,其生物半衰期分别为13分钟和42分钟。放射性在肾、肝含量最高,血浆、肺、心次之,肌肉、脾、睾丸、脑较低。静脉注射后,¹⁴C主要自尿排出(24小时可排出剂量的71.2%),自粪排出17.4%。口服后24小时可自尿排出34.3%,自粪排出33.1%。胆汁也是一条重要排泄途径,静脉注射后24小时可自胆汁排出剂量的47.4%;口服后相应时间内排出39.1%。本文所得结果与前文应用化学方法所得结果进行比较,表明自消化道、尿、胆汁所回收的放射性主要是黄豆甙元的代谢产物,说明该药在体内的代谢很旺盛。     

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.     

The metabolic disposition of C-labelled carmoisine in the rat after oral and intravenous administration

The absorption, distribution and excretion of the red azo dye carmoisine (Ext. D & C No. 10) was studied in male rats. [14C]Carmoisine was administered in a dose of 200 mg/kg (25 microCi) by gavage or in the same dose (200 mg/kg; 3 microCi) by intravenous injection, and radioactivity was measured in blood, tissue, faeces and urine at different times after dosing. After oral administration of the dye, no radioactivity was detected in the brain, adipose tissue, muscle, testes, spleen or lung, and recovery of the administered activity in faeces and urine was almost complete by 32 hr. The radioactivity profile of the blood indicated rapid but poor absorption of [14C]carmoisine, a maximum radioactivity content corresponding to 0.01% of the dose per ml of blood being reached within 10 min. The decay curve for 14C radioactivity in the blood after iv injection of [14C]carmoisine indicated rapid distribution to the tissues and could be described in terms of a two-compartment mathematical model. The highest levels of radioactivity occurred in the gastro-intestinal tract and liver after the injection but after 24 hr no radioactivity was detectable in these or other tissues. All the radioactivity was recovered in the faeces and urine in the 24 hr following iv injection, the 79% of the dose present in faeces indicating active excretion of the dye and its metabolites in the bile and poor reabsorption from the intestine. The bioavailability of [14C]carmoisine, calculated from the blood-radioactivity curves after oral and iv administration, was less than 10%.     

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.     

Absorption,Distribution, Metabolism,and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Orally to Rats

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [hexyl-1-¹⁴C] N-octylbicycloheptene dicarboximide (MGK 264).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered fhexyl-1-¹⁴C] MGK 264 at a single oral dose of 100 mg/kg, at a single oral dose of 1000 mg/kg, and at a daily oral dose of 100 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 100 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 100 mg/kg. Each animal was administered 18-30 μCi radioactivity.

Urine and feces were collected for all groups at predetermined time intervals. Seven days after dose administration, the rats were euthanized and selected tissues and organs were harvested. Samples of urine, feces, and tissues were subsequently analyzed for ¹⁴C content.

In the blood kinetics study, radioactivity peaked at approximately 4 h for the males and 6 h for the females. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity was approximately 8 h for males and 6 h for females.

Female rats excreted 71.45-73.05% of the radioactivity in urine and 20.87-25.28% in feces, whereas male rats excreted 49.49-63.49% of the administered radioactivity in urine and 31.76-46.67% in feces. Total tissue residues of radioactivity at 7 days ranged from 0.13 to 0.43% of the administered dose for all dosage regimens. The only tissues with ¹⁴C residues consistently higher than that of plasma were the liver, stomach, intestines, and carcass. The total mean recovered radioactivity of the administered dose in the studies ranged between 93.1 and 97.4%. No parent compound was detected in the urine.

Four major metabolites and one minor metabolite were isolated from the urine by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS). The four major metabolites were shown to be carboxylic acids produced by either ω-1 oxidation or β-oxidation of the side chain and oxidation of the norbornene ring double bond. The minor metabolite was the carboxylic acid of the intact norbornene ring.

The gender of the animals affected the rate, route of excretion, and metabolic profile. The urinary excretion rate was faster in females than in males and the amount excreted was also greater in female rats.     

Metabolism and elimination of benzocaine by rainbow trout,Oncorhynchus mykiss

1. Branchial and urinary elimination of benzocaine residues was evaluated in adult rainbow trout, Oncorhynchus mykiss, given a single dorsal aortic dose of ¹⁴C-benzocaine hydrochloride.

2. Branchial elimination of benzocaine residues was rapid and accounted for 59.2% of the dose during the first 3 h after dosing. Renal elimination of radioactivity was considerably slower; the kidney excreted 2.7% dose within 3 h and 9.0% within 24 h. Gallbladder bile contained 2.0% dose 24 h after injection.

3. Of the radioactivity in radiochromatograms from water taken 3 min after injection, 87.3% was benzocaine and 12.7% was N-acetylated benzocaine. After 60 min, 32.7% was benzocaine and 67.3% was N-acetylated benzocaine.

4. Of the radioactivity in radiochromatograms from urine taken 1 h after dosing, 7.6% was para-aminobenzoic acid, 59.7% was N-acetylated para-aminobenzoic acid, 19.5% was benzocaine, and 8.0% was N-acetylated benzocaine. The proportion of the radioactivity in urine changed with time so that by 20 h, 1.0% was para-aminobenzoic acid and 96.6% was N-acetylated para-aminobenzoic acid.

5. Benzocaine and a more hydrophobic metabolite, N-acetylated benzocaine, were eliminated primarily through the gills; renal and biliary pathways were less significant elimination routes for benzocaine residues.     

The Effect of Route of Administration on the Metabolic Fate of Terbutaline in the Rat

Abstract

1. The metabolic fate of [³H]terbutaline has been investigated in rats after oral, subcutaneous, intraperitoneal and intraportal administration (5 mg per kg).

2. About half the administered radioactivity was excreted in the urine and the remainder in faeces regardless of route of administration. Urinary excretion was essentially complete in 24 h, but an additional 10% of the dose was excreted in the 24–48 h faeces.

3. Only one metabolite, a glucuronide conjugate of terbutaline, was excreted in the urine along with unchanged drug. About 3% of the dose was excreted unchanged in urine following oral administration. Ratios of terbutaline glucuronide to free drug were 1 : 1, 2 : 1 and 13 : 1 after subcutaneous, intraperitoneal or intraportal, and oral administration respectively, suggesting that the orally administered drug is extensively conjugated in the intestinal mucosa.

4. Measurement of the mobility-pH profile by high-voltage paper electrophoresis was utilized to characterize the conjugate.     

Disposition and metabolism of [14C]lemborexant,a novel dual orexin receptor antagonist,in rats and monkeys

1. The disposition and metabolism of lemborexant, a novel dual orexin receptor antagonist currently under development as a therapeutic agent for insomnia disorder, were evaluated after a single oral administration of [¹⁴C]lemborexant in Sprague-Dawley rats (10?mg/kg) and cynomolgus monkeys (3?mg/kg).

2. In both species, [¹⁴C]lemborexant was rapidly absorbed: radioactivity concentration in blood peaked at 0.83–1.8?h, and decreased with elimination half-life of 110?h. The radioactivity administered was excreted primarily into faeces, with relatively little excreted into urine.

3. Lemborexant was not detected in bile, urine or faeces, indicating that lemborexant administered orally was completely absorbed from the gastrointestinal tract and that the main elimination pathway was metabolism in both species.

4. In rats, lemborexant was found to be minor in plasma (≤5.2% of total radioactivity), and M9 (hydroxylated form) was the major circulating metabolite. In monkeys, the major circulating components were lemborexant, M4 (N-oxide metabolite), M13 (di-oxidised form), M14 (di-oxidised form) and M16 (glucuronide of mono-oxidised form).

5. In both species, lemborexant was metabolised to various metabolites by multiple pathways, the primary of which was oxidation of the dimethylpyrimidine or fluorophenyl moiety.

     

Semi-quantitative profile of regioisomeric monohydroxydiphenylmethane metabolites in rat urine,faeces and bile

1. Urine and faeces, and two-hour bile samples from adult male rats dosed with [¹⁴C]diphenylmethane were analysed for benzhydrol and 2- and 4-hydroxydiphenyl-methane by silica gel GF t.l.c. and ¹⁴C-determination.

2. Mean values of 48.4% and 17.7% of the administered ¹⁴C were present in 24?h urine and faeces, respectively. Benzhydrol and 2- and 4-hydroxydiphenylmethane comprised 3.7%, 0.3% and 4.8% respectively of the ¹⁴C isolated from urine and 3.1%, 0.8% and 4.8% respectively of the ¹⁴C isolated from faeces.

3. Bile samples (2?h) contained 3.2% of the administered radioactivity. After treatment with β-glucuronidase/aryl sulphatase, 71.9% of the recovered biliary radioactivity was identified as benzhydrol (37.5%) and 4-hydroxydiphenylmethane (34.4%).     

The Metabolic Fate of the Coronary Dilator 4-(3,4,5-Trimethoxycinnamoyl)-1-(N-Isopropylcarbamoylmethyl)- Piperazine in the Rat,Dog and Man

1. An oral dose of the coronary dilator 4-(3,4,5-trimethoxycinnamoyl)-1- (N-isopropylcarbamoylmethyl)-piperazine was readily absorbed and more than 75% of the dose was excreted within 24 h by the rat, dog and man. In 4 days, rat, dog and man excreted in the urine and faeces respectively 32.5 and 62.3%, 43.9 and 49.1%, and 57.8 and 43.3%. Faecal radioactivity was mainly excreted via the bile.

2. Plasma concentrations of radioactivity reached a maximum within 1 h in rats and dogs and within 2 h in man. For several h, more than 50% of the radioactivity circulating in the plasma of rats and more than 80% in man was due to unchanged drug.

3. Sequential whole-body autoradiography of the rat indicated that much of the radioactivity was distributed in the liver, kidneys and gastrointestinal tract and that there was significant uptake into the heart and lungs.

4. Although similar metabolites were excreted by the rat, dog and man, the relative proportions differed. 11.7, 2.3 and 28.8% respectively of the unchanged drug were excreted in the urine and 13.1, 19.5 and 10.4% respectively of the principal metabolite a glucuronide whose exact structure was not determined. Other metabolites included 4-(3,4,5-trimethoxycinnamoyl)-1-carbamoylmethyl piperazine and N-(3,4,5-trimethoxycinnamoyl)-piperazine.