The distribution and excretion of [3H, 14C] lofepramine in the rat.

1. Lofepramine hydrochloride (N-methyl-N-[4-chlorobenzoylmethyl-3-(10, 11-dihydro-5H-dibenz(b,f)azepin-5-yl)]-propylamine hydrochloride) labelled with 3H in the dihydrobenzazepine moiety and 14C in the chlorobenzene moiety was synthesized and its distribution, urinary and biliary excretion were studied in female rats after oral administration. 2. For both isotopes, high ratios were established between tissues and blood. 3. Extensive N-dealkylation of lofepramine occurred in the rat. One of the metabolites, desmethylimipramine, was found in high concentrations in most tissues, especially the lungs and brain. 4. Desmethylimipramine was further metabolized to 2-hydroxydesmethyl-imipramine and 2-hydroxy-iminodibenzyl, and the corresponding glucuronides. These metabolites were mainly excreted via the bile. 5. p-Chlorobenzoic acid was found in the liver and lungs but not in the urine where most of the excreted 14C-activity was found. The identity of the major urinary metabolite is discussed.     

Disposition and metabolism of [14C]sparfloxacin in the rat.

Disposition and metabolism of [carbonyl-14C]sparfloxacin SPFX, 5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8-difluoro- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, AT-4140; CAS 110871-86-8), a novel antimicrobial quinolone, were studied in rats mainly after oral administration at 10 mg/kg. SPFX was absorbed from the whole area of small intestine as shown by the loop method. The extent of absorption was around 70% when estimated by AUC, urinary excretion and biliary excretion. Plasma level of radioactivity reached Cmax of 1.32 micrograms eq/ml within 1 h after oral administration and decreased with a half-life of about 4 h. Higher levels of radioactivity than that in plasma were seen in kidney, liver, submaxillary gland, lung, trachea and many other tissues and lower levels, in eye ball, brain and some others. Most tissue levels decreased with time essentially in parallel with plasma level. In pregnant rats, levels of fetal radioactivity amounted to about 60% of maternal plasma level. In lactating rats, milk was found to contain radioactivity several times as high as plasma level, which decreased with a similar half-life. SPFX was bound to plasma protein, mainly to albumin, at about 40%. Unchanged SPFX and its glucuronide were found in the plasma, milk, bile and urine. Within 48 h, about half of the dosed radioactivity was excreted in the bile, and part of which was re-absorbed. Within 96 h, about 20 and 80% of dose were found in the urine and feces, respectively.     

Disposition and metabolism of the colchicine derivative [14C]-ZD6126 in rat and dog

1. The tissue distribution, disposition and metabolism of ZD6126, a novel vascular targeting agent, were investigated in rat and dog. This paper comprises the findings of several investigations, including rat quantitative whole-body autoradiography (QWBA), rat and dog balance and metabolism (both in intact and bile-duct-cannulated animals), rat enterohepatic recirculation, and comparison of metabolism between young and mature rats. 2. Following intravenous administration of [(14)C]-ZD6126 to rats, quantitative whole-body autoradiography showed that radioactivity was widely distributed, then rapidly eliminated from the body. 3. ZD6126-related material was eliminated primarily in the faeces (approximately 86%) of both species, indicating the importance of biliary clearance. 4. Metabolite profiles from intact and bile-duct-cannulated animals suggest that ZD6126 is cleared primarily by metabolism. In rat, the major metabolites were ZD6126 phenol, its glucuronide and other metabolites consistent with O-demethylation and conjugation. ZD6126 was more extensively metabolized by male than female rats, and also in young compared with mature rats. In dog, metabolism occurred primarily via direct glucuronidation of the active species, ZD6126 phenol. 5. Following intraduodenal infusion of bile containing [(14)C]-ZD6126-related material to bile-duct-cannulated rats, 30% of the radioactivity was subsequently recovered in bile and urine, showing that one or more components in bile are reabsorbed and undergo enterohepatic recirculation.     

Absorption, distribution, metabolism and excretion of an inhalation dose of [14C] 4,4'-methylenediphenyl diisocyanate in the male rat

The received dose, tissue distribution, metabolism, routes and rates of excretion of [(14)C]-4, 4(')-methylenediphenyl diisocyanate (MDI) were investigated in the male rat following a 6-h inhalation exposure to [(14)C]-MDI at a target concentration of 2 mg m(-3). The mean dose received was equivalent to 0.078 mg MDI per animal, of this between 25 and 32% of radiolabelled material was available systemically. Radioactivity was distributed to all tissues examined with the highest proportions present in the respiratory and gastrointestinal tracts, suggesting that both oral ingestion and pulmonary absorption contributed to the systemic dose of [(14)C]-MDI derived material, with the oral ingestion and the majority of the internal dose resulting from ingestion of radiolabelled material by grooming the pelt after exposure. Radioactivity was excreted mainly via faeces (about 80% of the received dose). Excretion in bile and urine each accounted for less than 15% of the dose. MDI was extensively metabolized after uptake, with two routes of transformation evident; the proposed spontaneous formation of mixed molecular weight polyureas and the enzyme catalysed metabolism of systemically available MDI or MDI derivatives to give N-acetylated and N-acetylated hydroxylated products. No free MDA was detected in any of the biomatrices (urine, faeces, bile) investigated.     

Disposition of [14C]ruboxistaurin in humans.

Ruboxistaurin is a potent and specific inhibitor of the beta isoforms of protein kinase C (PKC) that is being developed for the treatment of diabetic microvascular complications. The disposition of [(14)C]ruboxistaurin was determined in six healthy male subjects who received a single oral dose of 64 mg of [(14)C]ruboxistaurin in solution. There were no clinically significant adverse events during the study. Whole blood, urine, and feces were collected at frequent intervals after dosing. Metabolites were profiled by high performance liquid chromatography with radiometric detection. The total mean recovery of the radioactive dose was approximately 87%, with the majority of the radioactivity (82.6 +/- 1.1%) recovered in the feces. Urine was a minor pathway of elimination (4.1 +/- 0.3%). The major route of ruboxistaurin metabolism was to the N-desmethyl ruboxistaurin metabolite (LY338522), which has been shown to be active and equipotent to ruboxistaurin in the inhibition of PKC(beta). In addition, multiple hydroxylated metabolites were identified by liquid chromatography-mass spectrometry in all matrices. Pharmacokinetics were conducted for both ruboxistaurin and LY338522 (N-desmethyl ruboxistaurin, 1). These moieties together accounted for approximately 52% of the radiocarbon measured in the plasma. The excreted radioactivity was profiled using radiochromatography, and approximately 31% was structurally characterized as ruboxistaurin or N-desmethyl ruboxistaurin. These data demonstrate that ruboxistaurin is metabolized primarily to N-desmethyl ruboxistaurin (1) and multiple other oxidation products, and is excreted primarily in the feces.     

The distribution,excretion and biotransformation of p-dichloro[14C]benzene in rats after repeated inhalation,oral and subcutaneous doses

1. Following repeated daily whole-body exposure (3h/day) of rats to atmospheres containing p-dichloro[¹⁴C]benzene (1000p.p.m.), or administration of oral or subcutaneous doses (250?mg/kg/day), 24-h tissue concn. of ¹⁴C were similar and did not increase after six days dosing, but tended to decrease.

2. After repeated daily atmospheric exposures or oral doses, highest concn. of ¹⁴C occurred in fat, kidneys, liver and lungs. Concn. declined rapidly to near or below limits of detection (< 0.2 p.p.m.) in plasma and tissues at 5 days. After similar subcutaneous doses, tissue concn. declined more slowly.

3. During five days after repeated dosing, most excreted ¹⁴C(91–97%) was in the urine. Little was excreted in faeces or expired air. Excretion was more prolonged following subcutaneous administration. After single doses to bile duct-cannulated animals, 46–63% of the excreted ¹⁴C was in the bile during 24h.

4. The pattern of metabolites in urine and bile was similar after each route of administration although there were quantitative differences. Urine extracts contained two major ¹⁴C-components, namely a sulphate and a glucuronide of 2,5-dichlorophenol, representing 46–54% and 31–34% of the urinary ¹⁴C respectively. Two minor components were identified by mass spectrometry as a dihydroxydichlorobenzene and a mercapturic acid of p-dichlorobenzene.

5. The glucuronide of 2,5-dichlorophenol was the major ¹⁴C component in bile (30–42%).     

Excretion and distribution of [14C]rhein and [14C]rhein anthrone in rat

After single intracaecal administration of [14C]rhein (25 mg kg-1) and [14C]rhein anthrone (20 mg kg-1) to rats, the summated recovery rates of 14C after five days were in urine 37(+/- 8.3)% and 2.8(+/- 0.4)% and in faeces 53(+/- 9.5)% and 95 (+/- 10.1)%, respectively. The clearance of radioactivity from the organs and tissues was almost complete within three days, with the exception of the kidney which exhibited pronounced retention of radioactivity even after five days (less than 61% of 24 h values). Extracts of faeces from animals treated with [14C]rhein of [14C]rhein anthrone, revealed rhein as well as other radioactive substances, which chemically did not react as 1,8-dihydroxyanthraquinones.     

Absorption, metabolism and distribution of [14C]-O-methyldopa and [14C]-L-dopa after oral administration to rats

1 The absorption, tissue distribution, and metabolism of [(14)C]-O-methyldopa were compared with those of [(14)C]-L-DOPA after oral administration to rats.2 Total radioactivity in the plasma and brain of rats treated with [(14)C]-O-methyldopa was significantly higher (2 fold and 30-50 fold, respectively) than that of rats treated with [(14)C]-L-DOPA.3 Total radioactivity in the gut washings and intestinal tissue 2 h after oral administration was significantly higher in rats treated with [(14)C]-L-DOPA than in rats treated with [(14)C]-O-methyldopa. The reverse was observed in the stomach tissues.4 Peripheral metabolism of [(14)C]-O-methyldopa was much lower than that of [(14)C]-L-DOPA; the major metabolite of [(14)C]-O-methyldopa in the plasma is L-DOPA, whereas L-DOPA is mainly metabolized to phenylcarboxylic acids.     

Absorption, distribution and metabolism of [14C]-levomenol in the skin

The purpose of the present investigations was to study the cutaneous absorption of sesquiterpenic alcohol, the major active principle of chamomile. For these investigations 14C-labelled levomenol ((-)-6-methyl-2-(4-methyl-3-cyclohexen-1-yl)-5-hepten-2-ol; (-)-alpha-bisabolol) was prepared by biochemical incorporation of [14C]-acetate into the molecule. 5 h after topical application of the radiolabelled substance onto nude mice half of the radioactivity was found in the skin. The other part was measured in tissue and organes. 90% of this radioactivity was analysed as intact levomenol. To demonstrate the distribution of the substance in the skin a part of this tissue was cutted into horizontal slices by a cryotome. From the slices autoradiograms were produced. The densitometric measuration showed that there was a fast penetration of levomenol into the skin. 5 h after the topical application the substance was displaced from outermost to innermost areas. From these results a fast cutaneous absorption and a long therapeutical effect of the antiphlogistic and spasmolytic levomenol in the skin can be expected.     

Placental transfer,excretion, and disposition of [14C]Zectran and [14C]Mesurol in maternal and fetal rat tissues

Pregnant Sprague-Dawley rats were injected ip on the 18th and 19th days of gestation with a tracer dose of [¹⁴C]Zectran (Z) or [¹⁴C]Mesurol (M). The excretion and distribution of total ¹⁴C were examined in fetal and maternal tissues. The distribution of Zectran and Mesurol after an ip dose was characterized by rapid maternal distribution and placental transfer. A distribution and elimination phase was seen for 30–60 min postinjection. After 1 hr [¹⁴C]Zectran in the whole fetus fell very slowly (K_e = 0.086 hr). At 15 min 1.7 and 3.5% of an administered dose of Zectran and Mesurol, respectively, was recovered from the pooled rat fetuses of a dam. After 8 hr, 0.8 and 1.1%, respectively, of the administered ¹⁴C was still present in the pooled fetuses. Fetal kidney and heart contained the most ¹⁴C after both Zectran and Mesurol administration. Liver was the maternal tissue with highest ¹⁴C content. More radioactive ¹⁴CO₂ derived from [¹⁴C]Zectran and [¹⁴C]Mesurol was exhaled by the nonpregnant rat (Z = 82.6%; M = 76.7%) than by the pregnant rat (Z = 62.2%; M = 66.9%). There was no significant difference in urinary excretion of ¹⁴C by pregnant or nonpregnant rats with either Zectran or Mesurol administration. Based on total ¹⁴C activity recovered in the urine, feces, and exhaled air after 8 hr, the pregnant animal retained 10.4–23% more ¹⁴C than the nonpregnant rat treated with either Zectran or Mesurol.     

Absorption, distribution, excretion and metabolism of a single oral dose of [14C]tri-o-cresyl phosphate (TOCP) in the male rat

A single oral dose of 50 mg/kg of [14C]TOCP was administered in corn oil to male rats. Three animals were sacrificed at each of 2, 6 and 12 h and 1, 2 and 5 days following dosing, and tissues and excreta were analyzed for 14C. Within 5 days, 63 and 36% of the dose were recovered in the urine and feces, respectively. Initially, the highest concentrations of radioactivity were observed in the gastrointestinal tract, its contents, the urinary bladder, liver and kidneys. Appreciable concentrations of 14C were detected in plasma, red blood cells, lungs and adipose tissues, while neural tissues, muscle, spleen and testes contained lower concentrations of radioactivity. Among neural tissues, the sciatic nerve contained the highest concentrations of 14C at all time points studied. The concentration of TOCP in plasma was at maximum by 6 h then declined biexponentially with terminal half-life of 46 h. The predominant metabolites in plasma were o-cresyl dihydrogen phosphate, di-o-cresyl hydrogen phosphate and o-hydroxybenzoic acid (salicylic acid). Small concentrations of the neurotoxic metabolite of saligenin cyclic-o-tolyl phosphate, were detected in plasma at all but the last time point analyzed. Most of the radioactivity extracted from the livers of rats sacrificed at 2 and 4 h were metabolites. No TOCP was detected in the urine or feces collected within 3 days after dosing. The major metabolite in the urine and feces was o-cresyl dihydrogen phosphate followed by di-o-cresyl hydrogen phosphate, salicylic acid, o-hydroxybenzyl alcohol and o-cresol. This study supports the hypothesis that the insensitivity of the rat to TOCP-induced delayed neurotoxicity may be attributed, in part, to the disposition and metabolism of this chemical.     

Absorption,distribution, metabolism and excretion of a new, 14C-labelled oxazolidinone MAO-A inhibitor in rat and dog

1. After oral administration of ¹⁴C-labelled (5R)-3-\[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone (E2011) at a dose of 1?mg/kg, the blood level of radioactivity reached a maximum concentration (C_max) of 0.545 μg eq./ml after 0.25?h in the rat and of 0.900 μg eq./ml after 0.5?h in the dog. In dog plasma, C_max for radioactivity and unchanged E2011 were 0.862 μg eq./ml and 0.650 μg/ml respectively with corresponding T_max (time at C_max) of 0.75 and 0.25?h. The unchanged drug in dog plasma was below the detection limit (5 ng/ml plasma) after 24?h. 2. The tissue levels of radioactivity were measured at 0.25 (T_max), 6, 24, and 168?h after max administration to the rat and at 0.5 (T_max), 24, and 168?h in the dog. The radioactivity was max distributed in all tissues examined at T_max in the rat and dog. The radioactivity levels of the cerebral cortex in the rat and dog were 26 and 36% of the plasma level at T_max. The radioactivity in tissues decreased at almost the same rate as that in plasma. Plasma protein binding of the unchanged drug in the rat in vitro were about 70% in the range of 0.1-10 μg/ml, and those in the dog were about 45% in the same concentration range. 3. Cumulative excretion of radioactivity in the rat was 74.5% in urine and 22.5% in faeces after 7 days. In the dog, 55.5 and 36.5% of the radioactivity administered were excreted in urine and faeces respectively after 7 days. The biliary excretion of radioactivity in the cannulated rat was 23.0% within 48?h. 4. In tlc analysis of plasma and tissues of the rat and dog, the radioactivity for the unchanged drug was much higher than metabolites. In tlc analysis of urine, the same metabolites were detected in the rat and dog, and the radioactivity of a metabolite, IM1, was the highest in the both animals. Eight metabolites were detected in the plasma, tissues and excreta of the rat, and four metabolites in the dog. 5. In conclusion, the absorption, distribution, metabolism and excretion of ¹⁴C-labelled E2011 in the rat and dog have been established, and only minor differences were observed between these species.