Intrinsic Lymphatic Partition Rate of Mepitiostane,Epitiostanol, and Oleic Acid Absorbed from Rat Intestine

Mepitiostane (MP), epitiostanol (EP), and oleic acid were administered to the jejunal loop of mesenteric vein- and thoracic duct-cannulated rats, and the intrinsic lymphatic partition rate (ILPR) of the absorbed compounds was directly determined. When ¹⁴C-EP was administered to the jejunal loop, recovery of unchanged EP in the mesenteric blood and the lymph was 7.9 and 0.03% of the administered dose, respectively. In contrast, following administration of ¹⁴C-MP, recovery of unchanged MP in the mesenteric blood and the lymph was 1.2 and 15.0%, respectively. Thus, following passage through the mucosal cell, 99.6% of the unchanged EP was partitioned into the blood and 0.4% into the lymph, while for unchanged MP, 7.6% was partitioned into the blood and 92.4% into the lymph. When ¹⁴C-oleic acid was administered to the jejunal loop, most of the penetrating oleic acid was incorporated into triglycerides in epithelial cells and transferred exclusively into the lymph. However, of the unchanged oleic acid, only 37.6% was partitioned into the lymph and 62.4% into the blood. The ILPR was 92.4% for MP, 0.4% for EP, and 37.6% for oleic acid. We conclude that the ILPR values indicate the true lymphotropic property of the compounds.     

Comparative evaluation of absorption,distribution, and excretion of YM758, a novel If channel inhibitor,between albino and non-albino rats

1. YM758 is a novel If channel inhibitor for the treatment of stable angina and atrial fibrillation. The absorption, distribution, and excretion of YM758 have been investigated in albino and non-albino rats after a single oral administration of ¹⁴C-YM758 monophosphate.

2. YM758 was well absorbed from all segments of the gastrointestinal tract except for the stomach. After oral administration, the ratio of AUC_{0–1 h} between the plasma concentrations of radioactivity and the unchanged drug was estimated to be 17.7%, which suggests metabolism.

3. The distribution of the radioactivity derived from ¹⁴C-YM758 in tissues was evaluated both in albino and non-albino rats. The radioactivity concentrations in most tissues were higher than those in plasma, which indicates that the radioactivity is well distributed to tissues. Extensive accumulation and slower elimination of radioactivity were noted in the thoracic aorta of albino and non-albino rats as well as in the eyeballs of non-albino rats. The recovery rates of radioactivity in urine and bile after oral dosing to bile duct-cannulated albino rats were 17.8% and 57.3%, respectively.

4. These results suggest that YM758 was extensively absorbed, subjected to metabolism, and excreted mainly into the bile after oral administration to rats, and extensive accumulation of the unchanged drug and/or metabolites into tissues such as the thoracic aorta and eyeballs was observed.     

Disposition and metabolism of a novel diurea inhibitor of acyl CoA: cholesterol acyltransferase (YM17E) in the rat and dog

We have investigated the disposition and metabolism of YM17E after intravenous and oral administration in the rat and dog.

2. Unavailability of YM17E was 5–9% at oral doses of 3–30 mg/kg in rat, and 9 and 13% at oral doses of 10 and 30mg/kg in dog.

3. Five N-demethylated metabolites, which have significant pharmacological activity, were found in rat and dog plasma after oral administration. Plasma concentrations of each of these metabolites were comparable with (hat of unchanged drug.

4. When ¹⁴C-YM17E was administered to rat, AUC of unchanged drug was 7% of that of radioactivity. However, AUC of the combined concentration of unchanged drug and five active metabolites was about 50% of that of radioactivity, indicating that the pharmacological activity of the agent was maintained in spite of its biotransformation.

5. After oral administration of ¹⁴C-YM17E at a dose of 10 mg/kg to rat, radioactivity was distributed widely to almost all tissues except the brain. The concentration of radioactivity in the liver, one of the target organs, was 65 times higher than that in plasma at 1 h after administration.

6. A significant amount of radioactivity in the liver was located in the microsomal subfraction, which contains much acyl CoA: cholesterol acyl transferase activity. More than 50% of this microsomal radioactivity was derived from unchanged YM17E and five active metabolites.

7. From excretion data in the bile duct-cannulated rat, the absorption ratio of YM17E from the gastrointestinal tract in this species was estimated to be at least 40%, suggesting that the low bioavailability of the drug is due to extensive first-pass metabolism.

8. Some 95% of the administered radioactivity was excreted in the faeces of rat following iv or po doses of ¹⁴C-YM17E.     

Metabolism of mephentermine in male guinea pigs and male mice

1. Urinary metabolites of mephentermine (MP), after i.p. administration of MP to male Hartley guinea pigs and mice, were identified by g.l.c.-electron impact (El) mass spectrometry. Excretion of urinary radioactivity, and metabolites of ³H-MP, after i.p. administration, were determined by preparative t.l.c.-liquid scintillation counting.

2. About 27% of the radioactivity administered was excreted in the 24?h urine of guinea pigs, and 36% dose was excreted in 5 days. In mice, about 47% of the radioactivity was excreted in the 24?h urine, and 52% in 5 days.

3. Excretion rates of metabolites detected in the 24?h urine of guinea pigs were phentermine (Ph, 7.8%), a conjugate of N-hydroxyphentermine (N-hydroxy-Ph, 3.6%), p-hydroxyphentermine (p-hydroxy-Ph, 1.0%) and its conjugate (2.9%), and other metabolites (conjugates of MP and Ph, N-hydroxymephentermine (N-hydroxy-MP) and its conjugate, p-hydroxymephentermine (p-hydroxy-MP) and its conjugate, and N-hydroxy-Ph; <1.0%). The rates of excretion for mice were Ph (11.7%), conjugates of p-hydroxy-MP (3.1%), Ph (2.7%) and p-hydroxy-Ph (1.6%), and N-hydroxy-Ph (1.2%) and other metabolites (conjugates of MP and N-hydroxy-Ph, N-hydroxy-MP and its conjugate, p-hydroxy-Ph, and p-hydroxy-MP; <1.0%).

4. These results indicate that MP administered to mice is metabolized mainly to Ph and p-hydroxy-MP by N-demethylation and p-hydroxylation of the parent compound, and in guinea pigs the primary metabolic reaction of MP is N-demethylation producing Ph. This, together with previous findings in rats, shows that there are marked metabolic differences between guinea pigs, mice and rats.     

Pre-systemic metabolism of viprostol in the monkey following oral and topical administration

1. ¹⁴C-Viprostol, (I), a synthetic PGE₂ analogue, was administered to 6 monkeys, orally, topically and intravenously in a three way crossover study. Total radioactivity and the pharmacologically active acid formed by rapid hydolysis of viprostol in vivo, (II), were measured in plasma to determine absorption and absolute bioavailability.

2. After oral dosing approx. 31% of drug-related radioactivity was absorbed. Systemic bioavailability of unchanged active acid was only 7˙3%. This indicates significant first-pass metabolism after oral administration, since only 23% of the absorbed radioactivity was available as ‘unchanged’ active drug (II).

3. After topical dosing, transdermal absorption of total radioactivity by 48 h averaged only 5% of dose. Absolute bioavailability of II averaged 3˙8% of dose. This indicates that after transdermal absorption 74% of the absorbed radioactivity was available systemically as the active acid II, with the remainder being subject to pre-systemic metabolism.     

Excretion of 14C-edrophonium and its metabolites in bile: Role of the liver cell and the peribiliary vascular plexus

1. The metabolism and biliary excretion of ¹⁴C-edrophonium chloride was studied in Wistar rat.

2. Approximately 5% of the dose was recovered from bile in 6 hours. Most of the radioactivity was eliminated as ¹⁴C-edrophonium glucuronide. Small amounts of the unchanged drug were also detected in bile, particularly during the first hour after administration of the drug.

3. The concentration of ¹⁴C-edrophonium glucuronide in bile was approximately 15-20 times its concentration in plasma.

4. In contrast, the concentration of unchanged ¹⁴C-edrophonium was similar in bile and plasma.

5. Evidence is presented that unchanged ¹⁴C-edrophonium is transferred from plasma to bile via the peribiliary vascular plexus.

     

Bioavailability and disposition of ‘H-solanine in rat and hamster

1. The toxicokinetics of [³H]-α-solanine after oral (p.o.) and intravenous (i.v.) administration in rat and hamster were studied, in order to decide which is the most appropriate model in risk assessment studies. The i.v. Dose was 54 βg/kg; the oral dose was 170 βg/kg.

2. After i.v. Administration, the toxicokinetics of total radioactivity in blood were comparable in rat and hamster. However, the clearance of total radioactivity from plasma was more effective in rat than in hamster. The half-lives of distribution and of the terminal phase of unchanged α-solanine were not different between rat and hamster, whereas the systemic and metabolic clearance were, respectively, about 1.6 and 2.7 times higher in rat than in hamster. The clearance of unchanged α-solanine is more effective than of total radioactivity.

3. After p.o. Administration in rat and hamster, the mean bioavailability of total radioactivity is about 29 and 57%, respectively. The bioavailability of unchanged α-solanine is only 1.6 and 3.2%, respectively, when compared with i.v. administration.

4. T_1/2el of α-solanine after p.o. Administration was in rats a factor of four and in hamsters a factor of two shorter than after i.v. Administration. A strong retention of radioactivity was seen in the hamsters after p.o. Administration; only 40% of the dose was excreted within 7 days versus 90% in rat.

5. Based on these and toxicological data from literature, it was decided that the hamster is a more appropriate model in (sub) chronic toxicity studies with α-solanine than the rat.     

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.     

The Metabolism of Tinidazole in the Rat and Dog

Abstract

1. [³⁵S]Tinidazole was administered to dogs and rats by oral and intravenous routes. Methods for the determination of tinidazole and total nitroimidazoles are described.

2. The main route for excretion of radioactivity was the urine in both species.

3. In the dog the serum contained predominantly unchanged drug.

4. In both species unchanged drug accounted for about half the urinary radioactivity; the remaining radioactivity was due to four metabolites.

5. One metabolite is the product of hydroxylation of the 2-methyl group and another is its O-glucuronide. The other two metabolites have not been identified, but they do not appear to be simple nitroimidazoles.

6. It is concluded that the metabolic fate of tinidazole is similar in dogs and rats.     

Studies on the Metabolism of Sympathomimetic Amines. The Metabolism of (±)-[14C]Noradrenaline in the Horse

Abstract

1. The metabolism of (±)-[¹⁴C]noradrenaline in horses has been studied. The plasma half-life of radioactivity following intravenous injection was 95 min.

2. Two horses each excreted about 80–85% of the radioactivity in the urine in 15 h after rapid intravenous injection and about 75% of the excreted radioactivity has been identified.

3. The unchanged drug in the urine accounted for less than 1% of the dose and 3-methoxynoradrenaline for about 7%. The main metabolites were 4-hydroxy-3-methoxymandelic acid (22%), 4-hydroxy-3-methoxybenzoic acid (13%) and 4-hydroxy-3-methoxyphenylglycol (11%). 3,4-Dihydroxyphenylglycol was a minor metabolite (5%).     

Absorption,distribution and excretion of lacidipine,a dihydropyridine calcium antagonist,in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog).

2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism.

3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug.

4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species.

5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses.

6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration.

7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Effect of potassium depolarization and preganglionic nerve stimulation on the metabolism of [3H]-choline in rat isolated sympathetic ganglia

1 The effects of potassium depolarization and preganglionic nerve stimulation on the metabolism of [³H]-choline in the isolated superior sympathetic ganglion of the rat have been studied.

2 When unstimulated (resting) ganglia were incubated for 10 min with a low concentration (0.1 μM) of [³H]-choline (high affinity uptake), approximately 75% of the accumulated radioactivity was present as [³H]-phosphorylcholine, 11% was [³H]-acetylcholine ([³H]-ACh) and the remainder was unchanged [³H]-choline.

3 Depolarization of the ganglia with K (46 mM) before their incubation with [³H]-choline, increased [³H]-choline uptake by 70% and increased [³H]-ACh synthesis by more than 700%, so that [³H]-ACh represented almost 50% of the total radioactivity recovered. In contrast, the proportion of [³H]-phosphorylcholine fell to 36% of the total radioactivity recovered.

4 The striking effect of K-depolarization on [³H]-ACh synthesis in ganglia occurred at a concentration of 30 mM or above, and the maximum effect was seen at 45-50 mM.

5 Chronic denervation of the ganglia abolished all the effects of high-K on [³H]-choline metabolism. In resting ganglia, [³H]-ACh formation was reduced by over 80% but [³H]-phosphorylcholine synthesis and the level of unchanged [³H]-Ch were not affected by denervation.

6 Exposure of the ganglia to low-Na or hemicholinium-3 (HC-3) greatly reduced [³H]-ACh synthesis in control resting ganglia and almost abolished the effects of high-K on [³H]-ACh synthesis.

7 Prevention of transmitter release with high-Mg or low-Ca medium also prevented K-depolarization from stimulating [³H]-ACh synthesis.

8 Preganglionic nerve stimulation had an effect on [³H]-choline metabolism similar to that of K-depolarization. Thus, at all the frequencies studied (1-30 Hz), [³H]-ACh synthesis was greatly increased and [³H]-phosphorylcholine was reduced, the maximum effects occurring at 3 Hz.

9 When ganglia were incubated with a high concentration (100 μM) of [³H]-choline (low affinity uptake), a different pattern of metabolism was observed. Most of the radioactivity in resting ganglia was present as unchanged [³H]-choline (70%) with [³H]-phosphorylcholine and [³H]-ACh representing 23% and 6% of the total radioactivity respectively. K-depolarization decreased [³H]-choline uptake but increased the proportions of [³H]-phosphorylcholine and [³H]-ACh to 32% and 24% of the total radioactivity respectively.

10 It is concluded that in unstimulated (resting) rat sympathetic ganglia most of the [³H]-choline transport and metabolism occurs in postsynaptic structures. However, depolarization of the presynaptic nerve terminals appears to trigger a sodium-dependent, HC-3 sensitive, high-affinity uptake process, and causes a dramatic increase in presynaptic [³H]-ACh synthesis together with a fall in postsynaptic [³H]-phosphorylcholine synthesis. These changes in choline metabolism cannot be due to the depolarization of the nerve terminals per se, because they were abolished by high-Mg or low-Ca, i.e. when transmitter release was prevented. Thus, the increase in ACh synthesis may be triggered by a fall in the intraterminal concentration of ACh or by the changes in Ca flux induced by depolarization. Our experiments do not provide evidence on these possible mechanisms.

     

Absorption,distribution, metabolism and excretion of the novel SARM GTx-024 [(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide] in rats

Abstract

1. GTx-024, a novel selective androgen receptor modulator, is currently being investigated as an oral treatment for muscle wasting disorders associated with cancer and other chronic conditions.

2. Absorption of GTx-024 was rapid and complete, with high oral bioavailability. A wide tissue distribution of [¹⁴C]GTx-024 derived radioactivity was observed. [¹⁴C]GTx-024-derived radioactivity had a moderate plasma clearance (117.7 and 74.5?mL/h/kg) and mean elimination half-life of 0.6?h and 16.4?h in male and female rats, respectively.

3. Fecal excretion was the predominant route of elimination, with ～70% of total radioactivity recovered in feces and 21–25% in urine within 48?h. Feces of intact rats contained primarily unchanged [¹⁴C]GTx-024 (49.3–64.6%). Metabolites were identified in urine and feces resulting from oxidation of the cyanophenol ring (M8, 17.6%), hydrolysis and/or further conjugation of the amide moiety (M3, 8–12%) and the cyanophenol ring (M4, 1.3–1.5%), and glucuronidation of [¹⁴C]GTx-024 at the tertiary alcohol (M6, 3.5–3.7%). There was no quantifiable metabolite in plasma.

4. In summary, in the rat GTx-024 is completely absorbed, widely distributed, biotransformed through several metabolic pathways, and eliminated in feces primarily as an unchanged drug.     

The Metabolites of Oxprenolol (Trasicor®) in man

Abstract

1. Two volunteers given a single oral dose of [³H]oxprenolol, excreted 70% and 95% of the radioactivity in the urine in 48 h. 78% and 71% of the urinary radioactivity is attributed to metabolites more polar than oxprenolol.

2. Metabolites, identified by mass spectrometry and isotope dilution analysis were as follows: I. the glucuronide of unchanged oxprenolol, II. a conjugate of a derivative of oxprenolol hydroxylated in the aromatic ring, III. unchanged oxprenolol, IV. the hydroxycarboxylic acid derived from oxprenolol by oxidative deamination, V. a carboxylic acid with the carboxyl group in the position of the former carbinol, VI. the monoallyl ether of catechol.     

Metabolism and kinetics of amlodipine in man

1. The disposition of amlodipine, R,S,2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine has been studied in two human volunteers using single oral and intravenous doses of ¹⁴C-amlodipine. The drug was well absorbed by the oral route while the mean oral bioavailability for unchanged drug was 62˙5%.

2. Renal elimination was the major route of excretion with about 60% of the dosed radioactivity recovered in urine. Mean total recovered radioactivity in urine and faeces amounted to 84% for both the oral and intravenous routes.

3. Apart from a small amount of unchanged amlodipine (10% of urine ¹⁴C), only pyridine metabolites of amlodipine were excreted in urine. The majority (<95%) of the metabolites excreted in the 0-72h post-dose period were identified; the major metabolite was 2-([4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-pyridyl]methoxy) acetic acid and this represented 33% of urinary radioactivity. The data indicate that oxidation of amlodipine to its pyridine analogue is the principal route of metabolism with subsequent metabolism by oxidative deamination, de-esterification and aliphatic hydroxylation.

4. For the two volunteers, amlodipine concentrations in plasma declined with a mean half-life of 33 h, while slower elimination of total drug-related material from plasma was observed, consistent with prolonged excretion (up to 12 days) of metabolites in urine and faeces. Only amlodipine and pyridine metabolites were found in the circulation. As these pyridine derivatives have minimal calcium antagonist activity the efficacy of amlodipine in man can most probably be attributed to the parent drug.     

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.     

Incorporation and metabolism of [14C]-arachidonic acid in guinea-pig lungs

1 Following infusion of [¹⁴C]-arachidonic acid into guinea-pig isolated lungs more than half the administered radioactivity was retained by the lung.

2 The majority of the retained radioactivity was present in the phospholipid fraction with lesser amounts in the neutral lipid and free fatty acid fractions. When fatty acid methyl esters of the phospholipid fraction were prepared, 80% of the radioactivity co-chromatographed with methyl arachidonate.

3 Transformation to cyclo-oxygenase products and subsequent emergence in lung effluent accounted for approximately 20% of infused radioactivity.

4 After pretreatment of lungs with [¹⁴C]-arachidonic acid, stimulation of arachidonic acid metabolism with injections of partially purified slow-reacting substance of anaphylaxis (SRS-A), bradykinin or antigen challenge released rabbit aorta contracting substance (RCS) and prostaglandin-like substances (PGLS) but little radioactivity. Furthermore, repeated injections of SRS-A or bradykinin released similar amounts of RCS and PGLS but diminishing amounts of radioactivity.

5 These data indicated that exogenous arachidonic acid was taken up by the lung and incorporated into phospholipids. However, this newly incorporated arachidonic acid had not equilibrated with the pool activated by SRS-A, bradykinin and antigen challenge for conversion to cyclo-oxygenase products.

     

Absorption,distribution and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats and dogs

1. The absorption, distribution and excretion of nilvadipine have been studied in male rats and dogs after an i.v. (1 mg/kg for rats, 0.1 mg/kg for dogs) and oral dose (10 mg/kg for rats, 1 mg/kg for dogs) of ¹⁴C-nilvadipine.

2. Nilvadipine was rapidly and almost completely absorbed after oral dosing in both species; oral bioavailability was 4.3% in rats and 37.0% in dogs due to extensive first-pass metabolism. The ratios of unchanged drug to radioactivity in plasma after oral dosing were 0.4–3.5% in rats and 10.4–22.6% in dogs. The half-lives of radioactivity in plasma after i.v. and oral dosing were similar, i.e. 8–10h in rats, estimated from 2 to 24 h after dosing and 1.5 d in dogs, estimated from 1 to 3 d. In contrast, plasma concentrations of unchanged drug after i.v. dosing declined biexponentially with terminal phase half-lives of 1.2 h in rats and 4.4 h in dogs.

3. After i.v. dosing to rats, radioactivity was rapidly distributed to various tissues, and maintained in high concentrations in the liver and kidneys. In contrast, after oral dosing to rats, radioactivity was distributed mainly in liver and kidneys.

4. With both routes of dosing, urinary excretion of radioactivity was 21–24% dose in rats and 56–61% in dogs, mainly in 24 h. After i.v. dosing to bile duct-cannulated rats, 75% of the radioactive dose was excreted in the bile. Only traces of unchanged drug were excreted in urine and bile.     

The Metabolism of Terbutaline in Dog and Rat

Abstract

1. The metabolic fate of [³H]terbutaline has been studied in dog after oral, intravenous and subcutaneous administration and in rat after oral and intravenous administration. In 3–4 days the dog excreted 75% of the dose in the urine after oral administration and more than 90% after intravenous or subcutaneous administration; the remainder was in the faeces. The rat in 24 h excreted about 13% in the urine and 61% in the faeces after oral administration and 48% in the urine and 35% in the faeces after intravenous administration.

2. After oral administration of [³H]terbutaline, the time course of radioactivity concentration was the same in lung, heart and serum; low levels of unchanged drug were found in all tissues. After intravenous administration, the concentration of unchanged drug was higher in lung and heart than in serum.

3. In dog, 1·7% of an intravenous dose was excreted into bile in 6 h. In rat, about 37% of the dose was recovered in the bile during 12 h.

4. Enzymic hydrolysis of urine showed that terbutaline is metabolized by conjugation, forming a glucuronide in rat but probably a sulphate in dog.     

Prostaglandin uptake and metabolism by the perfused rat liver

1. The prostaglandins are C20 unsaturated fatty acids which exhibit diverse physiological effects of short duration. We have investigated the speed of removal of PGE₁ and PGF_1α from the circulating blood and their subsequent metabolism by the isolated perfused rat liver.

2. Following either a single injection of radiolabelled PGE₁ or PGF_1α into the hepatic artery or portal vein, or recirculation of prostaglandins through the liver for 2·5 h, the distribution of radioactivity within extracts of bile, blood and liver was determined. The nature of the radioactive products of meta-bolism was inferred by comparison of the distribution of radioactivity after injecting carbon and tritium labelled standards, and by thin-layer chromatography, gas-liquid chromatography, ultraviolet and bioassay analysis.

3. A single injection of 1-¹⁴C PGE₁ indicated that the liver could efficiently remove 89-95% of circulating PGE₁ on a single passage. Biliary excretion was excluded as a major route for elimination of unchanged PGE₁, because only 0·3-0·8% of the injected radioactivity was detected in the bile. During recirculation of 1-¹⁴C PGE₁, 11-19% of the injected radioactivity was detected as exchanged ¹⁴CO₂. The radioactivity detected within liver was identified with further fragments resulting from decarboxylation of PGE₁, which were incorporated into fatty acids and then phospholipids.

4. Studies with 5,6-³H PGE₁, and comparison with the results obtained using 1-¹⁴C PGE₁, revealed a 30-fold increase in the percentage of radioactivity excreted into the bile, suggesting that biliary excretion may be a major route for elimination of compounds smaller than C20 prostaglandin. Evidence that the cyclopentane ring was intact was inferred by formation of a PGB compound on treatment with alkali; similar biliary excretion of 9-³H PGF_1α also occurred. In addition, the increased radioactivity detected within the liver (37%) and blood (43%) after a single injection of 5,6-³H PGE₁ had the solvent partition and thin-layer chromatography properties of PGE₁, but were associated with a less polar compound smaller than the C20 parent structure.

5. These results indicate rapid uptake of circulating prostaglandins by the rat liver. Decarboxylation of prostaglandins results in pharmacological inactivation. The products are excreted into the bile and venous effluent. These processes would curtail the duration of effects following prostaglandin injection.In addition, we infer from these results that any physiological action of these ubiquitous endogenous substances is likely to be localized within their tissue of origin.