Identification of turkey biliary metabolites of ractopamine hydrochloride and the metabolism and distribution of synthetic [14C]ractopamine glucuronides in the turkey

1. The bile duct cannulated turkey poult (n = 3) dosed orally with [¹⁴C]ractopamine HCl {(1R*,3R*),(1R*,3S*)-4-hydroxy-α-[[[3-(4-hydroxy[¹⁴C]phenyl)-1-methylpropyl]-amino]methyl]-benzenemethanol hydrochloride; 19.9 mg; 9.28 μCi] excreted 37.46 12.1% (mean ± SD) of the administered radioactivity in bile by 24 h post-dosing. 2. A mono-glucuronide, conjugated at C-10 (the methylpropylamino phenol) of ractopamine, accounted for 76.6% of biliary radioactivity. 3. Urine collected from the colostomized turkey poult (n = 3) orally dosed with synthetic [¹⁴C]ractopamine-glucuronides (10.1 mg; 3.6 μCi) contained 11.96 1.0% (mean ± SD) of the administered radioactivity 24 h after dosing, indicating that some absorption of radioactivity occurred. Faeces contained 60.6% of the administered radioactivity and carcasses (with gastrointestinal tracts) contained 23.3% of the starting radioactivity. 4. Five colostomized poults were fitted with bile duct cannulas and were dosed intraduodenally with 10.2?mg (3.6 μCi) synthetic [¹⁴C]ractopamine-glucuronides. Urine and bile contained 15.5 ± 2.2 and 16.8 ± 2.1% respectively of the administered radiocarbon by 24 h post-dosing. Faeces contained 54.3% of the administered radioactivity. Total absorption of the dosed radioactivity averaged 33.4%. 5. Bile and urine collected from the colostomized, bile-duct cannulated bird contained mainly ractopamine glucuronides. Indirect evidence suggests that the dosed ractopamine glucuronides were not absorbed intact.     

Hepatic uptake, disposition, and metabolism of rubratoxin B in isolated perfused rat liver

Isolated perfused rat liver preparations were utilized to measure the hepatic uptake, biliary excretion and metabolism of rubratoxin B. Livers were perfused with 30% rat blood perfusate containing 0.24 μmol labeled rubratoxin B, and a series of timed blood and bile samples were analyzed by high-pressure liquid chromatography, and treated enzymatically for the determination of glucuronide and sulfate conjugates. Blood, bile and liver samples were also radioassayed. Rubratoxin B was removed from the perfusate by a first-order process (monophasically) with a half-life of 207.5 ± 23.7 min (mean ± SE). By 3.5 hr of perfusion, 30% of the total rubratoxin B-derived radioactivity was excreted into the bile. More than 8% of the total dose of rubratoxin B was excreted unchanged into the bile by 3.5 hr. The rates of biliary excretion of rubratoxin B- derived radioactivity and parent compound reached a maximum at 30 min, after which time the rates of excretion decreased monophasically with half-lives of 35.5 and 72 min, respectively. Two major metabolites detected in the bile were the glucuronide and sulfate conjugates, together accounting for 22% of the radioactivity excreted into the bile by 3.5 hr. In addition, at least one major unidentified organosoluble metabolite was detected in the 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.     

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.     

Metabolism and excretion study of DW116, a new fluoroquinolone, in rats

Metabolite identification and urinary and biliary excretion of the new fluoroquinolone antibacterial agent DW116 [1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, hydrochloride] after oral administration have been studied in Sprague-Dawley rats. The excretion kinetics were monoexponential. Most of the drug was eliminated via the hepatic and renal routes. Mean renal clearance of DW116 was 73.4 ml/hr/kg and mean biliary clearance was 83.8 ml/hr/kg. The major metabolite excreted in the bile was identified as the glucuronide ester of the parent drug using base-hydrolysis of the conjugate metabolite followed by co-HPLC with standard compound,¹⁹F-NMR and LC-MS methods. The glucuronide conjugate was also found in urine. The mean urinary recoveries of free and total (free plus glucuronide ester) DW116 were 28.6±2.7% and 36.4±1.8% of the administered dose and the corresponding biliary recoveries were 14.4±5.5% and 37.0±7.6%, respectively.     

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.     

Trabectedin (Yondelis<Superscript>TM</Superscript>, formerly ET-743), a mass balance study in patients with advanced cancer

Trabectedin (Yondelis^TM, formerly ET-743) is an anti-cancer drug currently undergoing phase II development. Despite extensive pharmacokinetic studies, the human disposition and excretory pathways of trabectedin remain largely unknown. Our objective was to determine the mass balance of trabectedin in humans. To this aim, we intravenously administered [¹⁴C]trabectedin to 8 cancer patients, followed by collection of whole blood, urine and faeces samples. A 24-h infusion was administered to 2 patients, whereas the other 6 patients received a 3-h infusion. Levels of total radioactivity and unchanged trabectedin were determined and used for calculation of pharmacokinetic parameters. No schedule dependency of pharmacokinetic parameters was observed apart from C_max. Plasma and whole blood concentrations of [¹⁴C]trabectedin related radioactivity were comparable. Only 8% of the plasma exposure to [¹⁴C]trabectedin related compounds is accounted for by trabectedin, indicating the importance of metabolism in trabectedin elimination. Trabectedin displays a large volume of distribution (±1700 L), relative to total radioactivity (±220 L). [¹⁴C]trabectedin related radioactivity is mainly excreted in the faeces (mean: 55.5% of the dose). Urinary excretion accounts for 5.9% of the dose on average resulting in a mean overall recovery of 61.4% (3-h administration schedule). The excretion of unchanged trabectedin is very low both in faeces and in urine (< 1% of dose). In conclusion, trabectedin is extensively metabolised and principally excreted in the faeces.     

Biliary excretion and enterohepatic circulation of 1-nitropyrene metabolites in Fischer-344 rats

1-Nitropyrene (1-NP), present in diesel engine emissions, is a potent mutagen to bacteria, such as those found in mammalian intestinal tract, which contain nitroreductase enzymes. The purposes of this study were to determine the importance of bile as a route of excretion of 1-NP metabolites and to determine if reabsorption of biliary metabolites required the presence of intestinal bacteria. The bile ducts of male Fischer-344 rats were cannulated, 0.3 or 1.2 mumoles [3H]1-NP was given i.v., and bile, urine, and feces were collected for 24 hr. Biliary excretion accounted for 70 (80%) or 170 (60%) nmoles of [3H]1-NP after the low and high dose, respectively, with half-times for excretion of 1.7 hr +/- 0.3 (+/- S.E.M.) and 3.4 hr +/- 1.6 (+/- S.E.M.). Excretion of [3H]1-NP equivalents in the urine was linearly related to dose, with 6 or 16 nmoles (8%) excreted in 24 hr. At the low dose, more radioactivity appeared in the urine in control rats compared to bile-duct cannulated rats, suggesting that reabsorption of 1-NP metabolites occurred. Pretreatment of rats with orally administered antibiotics prior to i.v. injection of 0.3 mumole [3H]1-NP decreased radioactivity excreted in urine compared to untreated controls, suggesting that intestinal microorganisms may alter the biliary metabolites of 1-NP to facilitate reabsorption. Pretreatment of rats with buthionine sulfoximine, a glutathione depletor, decreased the excretion of certain biliary metabolites, suggesting that they were mercapturic acids of 1-NP metabolites. In summary, the results of these studies indicate that bile was an important route of excretion of nitropyrene metabolites. A portion of the excreted metabolites was reabsorbed from the gut, and this reabsorption required the presence of gut microorganisms.     

Metabolism of a glucuronide conjugate of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats

 Besides 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), [4-(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-β-O-d-glucosiduronic acid (NNAL-Glu) is another important metabolite of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) which has been detected in the urine of tobacco users and non-smokers heavily exposed to sidestream cigarette smoke. In order to evaluate the toxicological significance of NNAL-Glu formation and excretion, the metabolism of [5-³H]-NNAL-Glu was studied in rats. Five male F344 rats were administered 3.7 mg/kg [5-³H]-NNAL-Glu by i.v. injection and the metabolites in urine analysed by HPLC. More than 90% of the radioactivity was excreted in urine within the first 24 h. Unchanged NNAL-Glu accounted for 81.2±3.1% of the total radioactivity; the remaining part of the dose appears to be deconjugated resulting in the urinary excretion of NNAL (3.6±1.7%) and its α-hydroxylation (11.5±2.2%) and N-oxidation (3.6±1.6%) products. The presence of α-hydroxylation products of NNAL-Glu in urine suggests that this NNK metabolite may be activated in vivo to carcinogenic intermediates. Received: 25 April 1994 / Accepted: 29 June 1994     

Metabolism is an Important Route of Pentamidine Elimination in the Rat: Disposition of 14C-Pentamidine and Identification of Metabolites in Urine Using Liquid Chromatography-Tandem Mass Spectrometry

Abstract: This study assesses the contribution of metabolism for the disposition of pentamidine in the rat. With the use of ¹⁴C-labelled compound, the excretion of radioactivity in urine and faeces has been studied in four rats during 44 days after a single intravenous injection of the drug. The urinary and faecal excretion of the radioactivity were of equal importance; 22±2% (mean±S.D.) and 25±4% being detected in urine and faeces, respectively. The activity in organs and tissues at 44 days after drug administration was also measured and amounted to 21±5% of the administered dose. Using HPLC the proportion of metabolites in urine in relation to unchanged pentamidine increased with time after dose, being 76±15% (mean±S.D.) of the total excreted radioactivity on day 1 and 97±1% on day 6. HPLC - tandem mass spectrometry was used for identification of metabolites in urine obtained from four rats given unlabelled pentamidine. Using synthetic reference compounds and the selective MS/MS mode four oxidized metabolites of pentamidine were identified either by direct injection into the system or by analyses of extracted urine. Thus, a substantial part of pentamidine is excreted as metabolites in urine.     

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).     

Radioisotope studies of purine metabolism during administration of guanine and allopurinol in the pig

In pigs pre-fed guanine, some 33 per cent of [8-¹⁴C]guanine administered orally appeared in the urine in 24 hr, principally in the form of allantoin. Little incorporation (less than 1 per cent) of radioactivity into body tissues occurred and only 5 per cent of the radioactivity could be found in the faeces.When allopurinol was added to the guanine diet the pattern of excretion of [8-¹⁴C]-guanine changed considerably. Only 11 per cent of the radioactivity was recovered from the urine in 24 hr while 83 per cent appeared in the faeces in 3 days. Again, less than 1 per cent of the radioactivity was found in the tissues at slaughter.Intravenous administration of [8-¹⁴C]guanine to a pig on the above mixture resulted in the rapid incorporation of approximately 50 per cent of the radioactivity into body tissues with a slow subsequent daily excretion of approximately 2 per cent of this radioactivity in faeces and urine. The finding of 13 per cent of the radioactivity in the faeces is considered evidence of purine excretion into the gut. The recovery of urinary radioactivity (34 per cent of dose) principally in xanthine, but also in hypoxanthine, showed the existence of a rapid additional route of guanine catabolism via hypoxanthine. Experimental evidence is also presented to demonstrate the existence of a reciprocal relationship between urinary [¹⁴C]hypoxanthine and allopurinol riboside excretion suggesting competitive inhibition of allopurinol riboside formation by hypoxanthine in vivo.In the allopurinol treated pig, orally administered [6-¹⁴C]allopurinol was rapidly absorbed and almost totally excreted in the urine in 24 hr (90 per cent). The remainder of the radioactivity (approximately 7 per cent) was excreted in the faeces in 3 days and no radioactivity could be detected in tissue nucleic acids or in tissues to any extent (less than 0.01 per cent of the dose).The significance of these results in relation to the metabolic studies is discussed.     

Metabolism and excretion of [14C]taranabant,a cannabinoid-1 inverse agonist,in humans

1. Taranabant (N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide or MK-0364) is an orally active inverse agonist of the cannabinoid 1 (CB-1) receptor that was under development for the management of obesity. The metabolism and excretion of taranabant were investigated following a single oral dose of 5?mg/201 μCi [¹⁴C]taranabant to six healthy male subjects. The overall excretion recovery of the administered radioactivity was nearly quantitative (～?92%), with the majority of the dose (～?87%) excreted into faeces and a much smaller fraction (～?5%) into urine.

2. Taranabant was absorbed rapidly, with C_max of radioactivity attained at 1–2-h postdose. The parent compound and its monohydroxylated metabolite, M1, were the major radioactive components circulating in plasma and comprised ～?12–24% and 33–42%, respectively, of the plasma radioactivity for up to 48?h. A second monohydroxylated metabolite, designated as M1a, represented ～?10–12% of the radioactivity in the 2- and 8-h postdose plasma profiles.

3. Metabolite profiles of the faeces samples consisted mainly of the (unabsorbed) parent compound and multiple diastereomeric carboxylic acid derivatives derived from oxidation of the geminal methyl group of the parent compound and of the hydroxylated metabolite/s. These data suggest that, similar to rats and monkeys, taranabant is primarily eliminated in humans via oxidative metabolism and excretion of metabolites via the biliary/faecal route.

     

Elimination pathways of [14C]losoxantrone in four cancer patients.

Losoxantrone is an anthrapyrazole derivative in Phase III development in the U.S. for solid tumors, notably breast cancer. To obtain information on the routes of elimination of the drug, a study was conducted in four patients with advanced solid tumors, which involved intravenous administration of 100 microCi of [14C]losoxantrone for a total dose of 50 mg/m(2) during the first course of losoxantrone therapy. Blood, urine, and feces were collected for up to 2 weeks and were analyzed for total radioactivity and parent drug. In addition, feces were profiled for the presence of metabolites. Plasma concentrations of total radioactivity exhibited a temporal pattern similar to the parent drug. Combined recovery of administered total radioactivity from urine and feces was 70% with the majority (87%) of this radioactivity excreted in the feces, presumably via biliary excretion. Feces extracts were profiled for metabolites using a high-performance liquid chromatography method developed to separate synthetic standards of previously identified human urinary metabolites. Only intact losoxantrone was found in the feces. About 9% of the dose was excreted in the urine, primarily during the first 24 h and mostly in the form of parent compound. Collectively, these data indicate that fecal excretion of unmetabolized drug via biliary and/or intestinal excretion is the primary pathway of intravenously administered losoxantrone elimination in cancer patients with refractory solid tumors.     

Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys

DJ-927, currently undergoing Phase I clinical trial, is a new orally effective taxane with potent antitumor effects. The absorption, tissue distribution, and excretion of DJ-927 were investigated in mice, dogs, and monkeys after a single oral administration. After oral administration of [14C]DJ-927, radioactivity was rapidly absorbed, with the Cmax occurring within 1-2 h in all species. The blood and plasma radioactivity elimination was biphasic and species-dependent. Elimination half-life of plasma in dogs was much longer than those in monkeys or mice. In mice, radioactivity was rapidly distributed to all tissues except for the central nervous system, especially to adrenal glands, liver, pituitary glands, kidneys, lungs, and spleen. In all species, radioactivity was mainly excreted in feces. Following a single oral administration to mice, more than 80% of the radioactivity was excreted within 48 h; in dogs and monkeys, 80% of the radioactivity was excreted within 168 h. Urinary excretion was less than 7% of radioactive dose in all species. In vitro plasma protein binding of [14C]DJ-927 in the mouse, dog, and monkey plasma ranged from 92-98%. These studies showed that, the novel oral taxane DJ-927 was rapidly absorbed in all three species when administered by the oral route. The long biological half-life and slow elimination of radioactivity were distinctive in particular, compared with commercial taxanes. DJ-927 (as parent compound and its metabolites) is widely distributed to tissues except the brain. These preclinical data are useful for the design of clinical trials of DJ-927 and also for their interpretation.     

Distribution and biliary excretion of polychlorinated biphenyls in rats

Absorption, distribution, and excretion of two ³H-labeled polychlorinated biphenyls (PCB), 2,4,5,2′,4′,5′,-hexachlorobiphenyl (HCB) and 2,5,2′,5′-tetrachlorobiphenyl (TCB), were studied in surgically prepared male and female rats. Approximately 3–5 hr after surgery, HCB or TCB (50 mg/kg) was administered into the stomach. Bile, urine, and feces were collected for 24 hr after which the animals were sacrificed and tissues taken for determination of ³H content. The distribution of ³H remaining in the rats, expressed as percentage of dose, was highest in skeletal muscle, skin, liver, and small intestine for both isomers. The major difference observed between the PCBs was in biliary excretion. For HCB, 0.5 ± 0.2% (males, mean ± SE) and 1.1 ± 0.3% (females) of the dose were excreted in bile in 24 hr; for TCB, 42.2 ± 8.5% (males) and 25.7 ± 7.8% (females) were excreted by the same route. The lower biliary excretion of HCB than of TCB cannot be accounted for by a difference in absorption from the gastrointestinal tract and is thought to be due to a slower rate of HCB metabolism. More explicitly, the chlorines in the 4,4′ positions of HCB appear to prevent rapid biliary excretion of the compound by eliminating adjacent unsubstituted carbons which are necessary for rapid metabolism to occur. Urinary excretion of HCB and TCB was of minor importance compared to biliary excretion. Generally, absorption, distribution, and excretion of the PCBs were similar in males and females.     

The absorption,tissue distribution,and excretion of dodecyldimethylamine oxide (DDAO) in selected animal species and the absorption and excretion of DDAO in man

The absorption tissue distribution, and excretion pattern of [methyl-¹⁴C]DDAO and [1-dodecyl-¹⁴C]DDAO administered orally or cutaneously to rats, mice, and rabbits were investigated. The excretion pattern of radioactivity from [1-dodecyl-¹⁴C]DDAO administered orally and cutaneously to man was also investigated. An oral dose of DDAO is rapidly and extensively absorbed and excreted by rats and man. Peak tissue levels of radioactivity resulting from oral administration of [methyl-¹⁴C]DDAO to rats occur within 1 hr after dosing. Cutaneously administered DDAO is absorbed by man, rats, rabbits, and mice. In man, the rate of DDAO absorption through the skin is at least one order of magnitude less than that observed in rats, mice, and rabbits.     

Identification of turkey biliary metabolites of ractopamine hydrochloride and the metabolism and distribution of synthetic [14C]ractopamine glucuronides in the turkey

1. The bile duct cannulated turkey poult (n = 3) dosed orally with [14C]ractopamine HCl [(1R*,3R*),(1R*,3S*)-4-hydroxy-alpha-[[[3-(4-hydroxy[14C]phenyl)-1-methy lpropyl]amino]methyl]-benzenemethanol hydrochloride; 19.9 mg; 9.28 microCi] excreted 37.4 +/- 12.1% (mean +/- SD) of the administered radioactivity in bile by 24 h post-dosing. 2. A mono-glucuronide, conjugated at C-10 (the methylpropylamino phenol) of ractopamine, accounted for 76.6% of biliary radioactivity. 3. Urine collected from the colostomized turkey poult (n = 3) orally dosed with synthetic [14C]ractopamine-glucuronides (10.1 mg; 3.6 microCi) contained 11.9 +/- 1.0% (mean +/- SD) of the administered radioactivity 24 h after dosing, indicating that some absorption of radioactivity occurred. Faeces contained 60.6% of the administered radioactivity and carcasses (with gastrointestinal tracts) contained 23.3% of the starting radioactivity. 4. Five colostomized poults were fitted with bile duct cannulas and were dosed intraduodenally with 10.2 mg (3.6 microCi) synthetic [14C]ractopamine-glucuronides. Urine and bile contained 15.5 +/- 2.2 and 16.8 +/- 2.1% respectively of the administered radiocarbon by 24 h post-dosing. Faeces contained 54.3% of the administered radioactivity. Total absorption of the dosed radioactivity averaged 33.4%. 5. Bile and urine collected from the colostomized, bile-duct cannulated bird contained mainly ractopamine glucuronides. Indirect evidence suggests that the dosed ractopamine glucuronides were not absorbed intact.     

The Pharmacokinetics of Rimiterol in Man

1. The fate of [¹⁴C]rimiterol given orally, by aerosol, and intravenously to asthmatic patients has been investigated.

2. Following oral dosage (10?mg) < 50% dose was excreted in the urine. Two peaks in plasma concn. were seen, at 1–2 h and 3–5 h after dosing. Plasma radioactivity due to free rimiterol varied but never exceeded 10%. Of the urine radioactivity 50.5% was excreted as rimiterol (free and sulphate ester), and 30.5% as 3-O-methyl rimiterol (free and sulphate ester); free rimiterol accounted for only 1.7% and free 3-O-methyl rimiterol 2.5% of dose.

3. Following aerosol administration (0.39–0.56?mg) the pattern of metabolism and excretion was similar to that seen after oral administration.

4. After intravenous infusion (0.038 and 0.216 mg over 10 min) 92% of dose was excreted in the urine, suggesting little biliary excretion. Peak plasma concn. were seen 2–4?min after the end of injection at which time most of the radioactivity was due to free rimiterol. Of the urine radioactivity, 28.45% was excreted as rimiterol (free and sulphate ester), and 44.9% as 3-O-methyl rimiterol (free and sulphate ester), with 26.5% as unchanged rimiterol. Thus after intravenous administration a greater amount of free drug was excreted and a higher percentage of the dose was 3-O-methylated.     

Beta-cyclodextrin reduces bioavailability of orally administered [3H]benzo[a]pyrene in the rat

The excretion and plasma kinetics of total radioactivity were studied following single oral administration of [(3)H]benzo[a]pyrene after multiple oral administration of beta-cyclodextrin at 0, 5, 50, or 500 mg/kg/day. The AUC and C(max) values in male and female rats following administration of [(3)H]benzo[a]pyrene in combination with 5 to 500 mg/kg beta-cyclodextrin were considerably lower than that in rats administered [(3)H]benzo[a]pyrene alone. At all dose levels of beta-cyclodextrin, the excretion of total radioactivity was almost entirely via feces, with <2% recovered in urine, demonstrating either that absorption of the orally administered dose was low or that, for any absorbed material, biliary excretion was the main route of excretion. However, following administration of vehicle, up to 5% of the administered radioactivity was recovered in the urine, suggesting that absorption may have been reduced by the presence of beta-cyclodextrin in the intestine. At all dose levels of beta-cyclodextrin, there was minimal retention of radioactivity in the carcase at the end of the collection period. Beta-cyclodextrin did not affect the apparent terminal half-life of radioactivity. Therefore, the reduced systemic exposure of rats to radioactivity in the presence of beta-cyclodextrin is likely related to a reduced oral bioavailability.