Biotransformation and mass balance of faldaprevir,a hepatitis C NS3/NS4 protease inhibitor in rats

Abstract

1.?The metabolism, pharmacokinetics, excretion and tissue distribution of a hepatitis C NS3/NS4 protease inhibitor, faldaprevir, were studied in rats following a single 2?mg/kg intravenous or 10?mg/kg oral administration of [¹⁴C]-faldaprevir.

2.?Following intravenous dosing, the terminal elimination t_1/2 of plasma radioactivity was 1.75?h (males) and 1.74?h (females). Corresponding AUC_0–∞, CL and V_ss were 1920 and 1900?ngEq?·?h/mL, 18.3 and 17.7?mL/min/kg and 2.32 and 2.12?mL/kg for males and females, respectively.

3.?After oral dosing, t_1/2 and AUC_0–∞ for plasma radioactivity were 1.67 and 1.77?h and 11?300 and 17?900 ngEq?·?h/mL for males and females, respectively.

4.?In intact rats, ≥90.17% dose was recovered in feces and only ≤1.08% dose was recovered in urine for both iv and oral doses. In bile cannulated rats, 54.95, 34.32 and 0.27% dose was recovered in feces, bile and urine, respectively.

5.?Glucuronidation plays a major role in the metabolism of faldaprevir with minimal Phase I metabolism.

6.?Radioactivity was rapidly distributed into tissues after the oral dose with peak concentrations of radioactivity in most tissues at 6?h post-dose. The highest levels of radioactivity were observed in liver, lung, kidney, small intestine and adrenal gland.     

Absorption,distribution, metabolism and excretion of gemigliptin,a novel dipeptidyl peptidase IV inhibitor,in rats

Abstract

1.?The absorption, distribution, metabolism and excretion of a novel dipeptidyl peptidase IV inhibitor, gemigliptin, were examined following single oral administration of ¹⁴C-labeled gemigliptin to rats.

2.?The ¹⁴C-labeled gemigliptin was rapidly absorbed after oral administration, and its bioavailability was 95.2% (by total radioactivity). Distribution to specific tissues other than the digestive organs was not observed. Within 7 days after oral administration, 43.6% of the administered dose was excreted via urine and 41.2% was excreted via feces. Biliary excretion of the radioactivity was about 17.7% for the first 24?h. After oral administration of gemigliptin to rats, the in vivo metabolism of gemigliptin was investigated with bile, urine, feces, plasma and liver samples.

3.?The major metabolic pathway was hydroxylation, and the major circulating metabolites were a dehydrated metabolite (LC15-0516) and hydroxylated metabolites (LC15-0635 and LC15-0636).     

Localization and disposition of a non-peptide angiotensin II type 1 receptor antagonist,and its glucuronide metabolite,in rat

1. The disposition of radioactivity of a non-peptide angiotensin II type 1 receptor antagonist (E4177) has been studied in groups of male rats after a single oral 1?mg/kg dose of ¹⁴C-E4177 was administered by gavage. We have also used light-microscopic autoradiography to investigate the localization of radioactivity in the target tissues for this angiotensin II receptor antagonist. 2. The radioactivity was absorbed quickly, and the maximum blood levels (C_max) were reached at 0·38 ± 0·14?h after dosing. The concentrations then declined bi-exponentially with a mean apparent half-life for the first phase (t_½α) of 0·46 ± 0·07?h and a terminal half life (t_½β) of 6·22 ± 1·08?h. By 24 h, the levels had decreased to 2·7 ± 1·5% C_max. The blood beta max levels radioactivity at 48?h after administration were below the limit of quantification. 3. Radioactivity was distributed throughout the body at 15?min after administration. Tissues inwhich radioactivity was present at higher levels thaninplasma were the liver and kidney. Radioactivity was rapidly eliminated from the tissues and was not retained in any individual organ. 4. The major route of excretion was via the bile. Since > 90% of the administered radioactivity was recovered by 24?h after administration, the excretion was relatively rapid. The major metabolite in bile was a glucuronide of E4177 biphenylcarboxylic acid (E4177- Glu). 5. Light-microscopic autoradiographic observations revealed a strong localization of radioactivity throughout the surface cells of the adrenal glomerulosa, the blood vessels in kidney and the surface of the aortic smooth muscle cells, which are all rich in angiotensin II type 1 (AT1) receptors.     

Studies on Metabolism of Trazodone,I. Metabolic Fate of [14C]Trazodone Hydrochloride in Rats

Abstract

1. One of the main metabolites of [¹⁴C]trazodone hydrochloride by rat liver in vitro is hydroxylated trazodone.

2. [¹⁴C]Trazodone HCI is absorbed very rapidly and the blood level of radioactivity attains a maximum within 15 min after oral administration of 4 mg/kg to rats and thereafter decreases rapidly.

3. Urinary and faecal excretions of radioactivity are 49.0 and 46.1% of the dose respectively, during the first 7 days after ingestion, and biliary excretion is 80.0% in 8 h.

4. After oral administration of [¹⁴C]trazodone HCI to rats the main metabolites in urine and bile are hydroxylated trazodone, β-{3-oxo-s-triazolo[4,3a]-pyridin-2-yl}-propionic acid and their glucuronides.

5. Unchanged and hydroxylated trazodone alone are present in brain of rats after oral administration (20 mg/kg); both compounds in brain decrease with similar half-lives to those in plasma.     

Distribution and elimination of the herbicide propanil in the Channel Catfish (Ictalurus punctatus)

1. The uptake, elimination and tissue distribution of total radioactivity derived from the herbicide, [¹⁴C]propanil (3,4-dichloropropionanilide) and its metabolites were examined in individual farm-raised Channel Catfish which were exposed for 24?h to water containing 1 ppm of ¹⁴C-propanil under static conditions. Uptake and elimination of total radioactivity was monitored in individual animals over time in respective exposure (24?h) and depurating (144?h) aquaria.

2. Maximal uptake was reached between 8 and 12?h with approx. 38% of the absorbed radioactivity remaining in the animal after 144?h of depuration. Whole body depuration of radioactivity was biphasic with a and β half-lives of 20 and 444?h, respectively.

3. Tissue distribution of total radioactivity was monitored at various time points in 12 tissues and bile over 48?h. Intestine, abdominal fat and liver possessed the greatest levels of radioactivity per gram of tissue over time. Radiolabel was shown to slowly increase in bile and intestine indicating biliary excretion as a possible pathway of metabolite elimination.

4. Bile possessed approx. 104 nmol (23%) of the remaining radioactivity in fish after 48?h. Other whole tissues possessing > 10% of radiolabel after 48?h were blood (83.5 nmol, 19% of the administered dose) and muscle (190 nmol, 43%).     

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.     

Absorption,Excretion and Metabolism of a New Dihydropyridine Diester Cerebral Vasodilator in Rats and Dogs

1. After oral administration of [¹⁴C]dihydropyridine diester, the plasma concn. of radioactivity was similar in rats and dogs, reaching a maximum at 0·5 to 1?h and decreasing with a half life of about 3·5 h. The plasma concn. of unmetabolized drug in dogs was 10 times higher than in rats. Radioactivity in rat tissue was high in liver, kidney and lung after both oral and intravenous administration.

2. In both species, 66–72% of radioactivity was excreted in faeces and 23–29% in urine in 48?h, regardless of the route of administration. Biliary excretion in rats after oral dosage amounted to 65%.

3. Eight metabolites were identified from urine of dogs and rats. They were derived from one or several of the following pathways: I, debenzylation of the N-benzyl-N-methylaminoethyl side chain; II, reduction of the 3-nitro group on the phenyl substituent; III, oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine; IV, oxidative removal of the N-benzyl-N-methylamino group yielding a carboxylic acid; V, hydrolysis of the N-benzyl-N-methylamino-ethyl ester to the corresponding carboxylic acid; VI, hydroxylation of the 2-methyl group of the 1,4-dihydropyridine ring to hydroxymethyl.     

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.     

The comparative disposition and metabolism of dolutegravir,a potent HIV-1 integrase inhibitor,in mice,rats, and monkeys

Abstract

1.?Plasma clearance of dolutegravir, an unboosted HIV-1 integrase inhibitor, was low in rat and monkey (0.23 and 2.12?mL/min/kg, respectively) as was the volume of distribution (0.1 and 0.28?L/kg, respectively) with terminal elimination half-life approximately 6?h. Dolutegravir was rapidly absorbed from oral solution with a high bioavailability in rat and monkey (75.6 and 87.0% respectively), but solubility or dissolution rate limited when administered as suspension.

2.?Dolutegravir was highly bound (>99%) to serum proteins in rat and monkey, similar to binding to plasma and serum proteins in human. Radioactivity was associated with the plasma versus cellular components of blood across all species.

3.?Following oral administration to rats, [¹⁴C]dolutegravir-related radioactivity was distributed to most tissues, due in part to high permeability; however, because of high plasma protein binding, tissue to blood ratios were low. In mouse, rat and monkey, the absorbed dose was extensively metabolized and secreted into bile, with the majority of the administered radioactivity eliminated in feces within 24?h.

4.?The primary route of metabolism of dolutegravir was through the formation of an ether glucuronide. Additional biotransformation pathways: benzylic oxidation followed by hydrolysis to an N-dealkylated product, glucose conjugation, oxidative defluorination, and glutathione conjugation.     

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 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.     

Investigation of disposition for TAK-448, a synthetic peptide of kisspeptin analog,in rats and dogs using the radiolabeled TAK-448 suitable for pharmacokinetic study

1. Disposition of 2-(N-acetyl-d-tyrosyl-trans-4-hydroxy-l-prolyl-l-asparaginyl-l-threonyl-l-phenylalanyl) hydrazinocarbonyl-L-leucyl-N^ω-methyl-l-arginyl-l-tryptophanamide monoacetate (TAK-448, RVT-602), a synthetic kisspeptin analog, was investigated after parenteral dosing of radiolabeled TAK-448 ([d-Tyr-¹⁴C]TAK-448) to rats and dogs, and it was confirmed if the radiolabeling position at d-Tyr was eligible for assessment of in vivo disposition.

2. Dosed radioactivity was rapidly and well absorbed after subcutaneous administration and an appreciable amount of unchanged TAK-448 (TAK-448F) and a hydrolyzed metabolite, M-I, were detected in the plasma of rats and dogs.

3. After intravenous administration of [d-Tyr-¹⁴C]TAK-448 to rats, the radioactivity widely distributed to tissues with relatively higher concentrations in kidney and urinary bladder.

4. The radioactivity was decreased rapidly from the tissues.

5. After subcutaneous administration of [d-Tyr-¹⁴C]TAK-448 to rats and dogs, the dosed radioactivity was almost completely recovered by 48 and 72?h in rats and dogs, respectively, and most of the radioactivity was excreted in urine after extensive metabolism in the two species.

6. These results suggest that TAK-448 has an acceptable pharmacokinetic profile for clinical evaluation and development, and demonstrate that the synthesized [D-Tyr-¹⁴C]TAK-448 used in this study represents a favorable labeling position to evaluate disposition properties of this compound.

     

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.     

Stereoselective Metabolic Disposition of Enantiomers of Ofloxacin in Rats

1. Stereoselective metabolic disposition of ofloxacin (OFLX) was studied in rats after oral administration of S-(-)-¹⁴C-OFLX and R-(+)-¹⁴C-OFLX at a dose of 20mg/kg.

2. Radioactivity of the S-(-)-isomer was eliminated from blood much faster than that of the R-(+)-isomer. Marked differences in pharmacokinetic parameters exist between the enantiomers; the half life and AUC values of R-(+)-OFLX were greater than those of S-(-)-OFLX. Enantiomeric differences were also seen in the excretion of radioactivity, especially in biliary excretion.

3. 31.3 and 7.4% dose were excreted in the 8?h bile as ester glucuronides after oral administration of S-(-)- and R-(+)-OFLX, respectively. The enantiomeric difference in biliary excretion may be caused by stereoselective glucuronidation of S-(-)-OFLX to the ester glucuronide.

4. The metabolite pattern in serum and urine showed that the ester glucuronide of S-(-)-OFLX was more predominant than that of R-(+)-OFLX.

5. The stereoselective ester glucuronidation of the S-(-)-isomer in rats may induce significant differences in the pharmacokinetic parameters of S-(-)- and R-(+)-OFLX.     

Disposition and metabolism of (2S,3S,4R)-N′′-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxy methyl-2H-benzopyran-4-yl)-N′-benzylguanidine,a novel neuroprotective agent for ischemia-reperfusion damage,in rats

The metabolism and disposition of KR31378 (a benzopyran derivative and a novel neuroprotective agent) were investigated following single oral or intravenous administration of [¹⁴C]-KR31378 to rats. [¹⁴C]-KR31378 was rapidly absorbed after oral dosing with an oral bioavailability of greater than 71%. The maximum plasma concentration and area under the curve of total radioactivity in rat plasma increased proportionally to the administered dose. KR31378 was distributed over all organs and tissues except for brain, eyeball and testis, and declined by first order kinetics up to 24?h after dosing. Excretion of the radioactivity was 29.5% of the dose in the urine and 58.5% in the feces within 2 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 66.0% for the first 24?h. KR31378 was extensively metabolized by ring hydroxylation, O-demethylation, oxidation and reduction with subsequent N-acetylation and O-glucuronide conjugation. N-acetylated conjugates (M2, M10, M11, M12, M14, and M15) were identified as the predominant metabolites in rats.     

Absorption and disposition of epithiosteroids in rats (2): Avoidance of first-pass metabolism of mepitiostane by lymphatic absorption

1. Absorption of mepitiostane (MP) from the gastrointestinal tract was examined using thoracic duct-cannulated rats.

2. When ¹⁴C-MP was administered into the small intestine, 34% of the radioactivity was recovered in the 6-h thoracic duct lymph. More than 90% of this radioactivity was due to unchanged MP and most of the MP in the lymph was carried in the lipid core of the chylomicrons and VLDL.

3. Radioactivity in the portal blood was extensively extracted by the liver and excreted into bile as polar metabolites. Thus, most unchanged MP which entered the systemic circulation following oral administration was drug absorbed via the intestinal lymphatics.

4. MP avoids the first-pass effect by lymphatic adsorption.     

Absorption,distribution, metabolism and excretion of loxoprofen after dermal application of loxoprofen gel to rats

Abstract

1. Loxoprofen (LX), is a prodrug of the pharmacologically active form, trans-alcohol metabolite (trans-OH form), which shows very potent analgesic effect. In this study, the pharmacokinetics and metabolism of [¹⁴C]LX-derived radioactivity after dermal application of [¹⁴C]LX gel (LX-G) to rats were evaluated.

2. The area under concentration-time curve (AUC_0–∞) of radioactivity in the plasma after the dermal application was 13.6% of that of the oral administration (p?<?0.05).

3. After the dermal application, the radioactivity remained in the skin and skeletal muscle at the treated site for 168?h, whereas the AUC_0–168?h of the radioactivity concentration in every tissue examined except the treated site was statistically lower than that after the oral administration (p?<?0.05).

4. The trans-OH form was observed at high levels in the treated skin site at 0.5?h. Metabolite profiles in plasma, non-treated skin site and urine after the dermal application were comparable with those after the oral administration.

5. Renal excretion was the main route of elimination after the dermal application.

6. In conclusion, compared to the oral administration, the dermal application of [¹⁴C]LX-G showed lower systemic and tissue exposure with higher exposure in the therapeutic target site. The radioactivity revealed similar metabolite profiles in both administration routes.     

10-羟基癸烯酸在动物体内吸收、分布、代谢和排泄

10-癸基癸烯酸(即10-HDA,定位标记为³H-10HDA),经小鼠和大鼠口服后,胃肠道吸收快,峰时均在1h,全身分布迅速广泛,与组织亲和力强,肝中放射性为最高,依次为肾、胰、脂肪、脑、脾、心和肺。平均Vd为9.71/kg。Ig和iv的T1/2β在12.6～22.7h。体内消除较缓慢,31 d内,尿粪中放射性累计排泄分别为给药量的85.4%和13.5%,提取尿和胆汁经分析结果主要以原形药物排出。血浆蛋白结合率为63%。血中放射—性时间曲线符合开放二室模型。     

Percutaneous absorption of [14C]methacrylamide in animals

Percutaneous absorption of [^l4C]methacrylamide was determined in rabbits, rats and mice. Radioactivity in blood of rabbits increased rapidly after IV injection, after topical application with a cloth and after direct topical application of a 15 or 5% test solution, suggesting high permeability of the skin for methacrylamide. Radioactivity then began to decrease exponentially within 1 h. Tissue radioactivity 24 h after IV dosing was high in blood, liver and serum, and low in brain, nerve and muscle. The radioactivity was more uniformly distributed with the exception of liver, after application with a cloth and after direct contact than after IV dosing. When the application site was washed with water after direct application, decline of radioactivity in blood was accelerated slightly and a decrease in radioactivity in some tissues was found, although the difference between non-wash and wash groups was not significant in either the declining curve or the tissue radioactivity, with the exception of serum for the latter. Between 25 and 60% of the radioactivity found in tissues was protein-bound after 24 h. Recovery of radioactivity in urine was highest after IV administration, intermediate after direct contact, and lowest after cloth application. Radioactivity in expired air and bile was small. Both radioactivity in tissues and its recovery in urine in rats, and tissue radioactivity in mice, were lower than in rabbits, when adjusted for dose per unit body weight, suggesting lower skin permeability for methacrylamide in the former species. In rats, radioactivity in some tissues was significantly decreased after washing. An autoradiographic study on rabbit skin indicated that the test material penetrated the skin largely through hair follicles.     

Kinetics and disposition of picumeterol in animals

1. The pharmacokinetics and disposition of picumeterol, a novel β₂ receptor agonist agent, have been studied in the rat and dog following administration by inhalation, intravenous and oral routes at various dose levels.

2. Picumeterol was found to be transferred across the lung of the rat and dog following inhalation dosage. After i.v. dosage picumeterol was eliminated from plasma with a half-life of about 1?h in the rat and about 2?h in the dog. Plasma clearance in the rat was about twice liver blood flow and the plasma levels of picumeterol were low after oral administration.

3. Following instillation of ¹⁴C-picumeterol to the trachea of isolated respiring rat lung preparations radioactivity was transferred from the airways to perfusion media as unchanged drug within 2?min. After 2?h perfusion, no metabolites were detected in the recirculation perfusate or lung.

4. Picumeterol was extensively metabolized in vivo in the rat (about 95%) and dog (about 90%) and in vitro in microsomal preparations of rat, dog and human liver. O-dealkylation and β-oxidation are important as routes of metabolism.

5. Radioactivity was largely excreted in the urine of the rat and dog (> 50% of dose), as metabolites, following i.v. administration. There was some excretion of radioactivity in dog bile. Extensive first-pass metabolism was found after oral administration in the rat.