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.     

Metabolism of 6-Chloro-5-cyclohexylindane-1-carboxylic Acid (TAI-284), a New Non-steroidal Anti-inflammatory Agent. I. Absorption,Distribution and Excretion in Rats

Abstract

1. In rats, a new non-steroidal anti-inflammatory agent, 6-chloro-5-cyclohexylindane-1-carboxylic acid (TAI-284), labelled with ³H, was almost quantitatively absorbed, mainly from the small intestine. Gastric absorption was also demonstrated.

2. The plasma concn. of the orally administered drug reached a peak at 2 h with a half-life of about 7·5 h. The concn. after intravenous injection decreased biphasically with t_0·5 values of 20 and 80 min. About half of the plasma radioactivity was the intact drug, of which more than 90% was bound to plasma protein. Plasma metabolites, detected by t.l.c., were the 4′-oxocyclohexyl derivative (I), a mixture of cis-4′- and cis-3′-hydroxycyclohexyl derivatives (IIa and IIb), trans-4′-hydroxycyclohexyl derivative (III) and cis-3′-hydroxycyclohexyl derivative (IV), together with small amounts of unidentified polar metabolites (V and VI). Metabolites IIb and IV are diastereoisomers.

3. TAI-284, administered orally or intravenously, was widely distributed, with high concn. in stomach, duodenum, liver, small intestine, adrenal and kidney, but far less in brain. The concns. in most tissues were lower than the blood level. Distribution of radioactivity in inflamed tissues was also demonstrated.

4. Oral TAI-284 was completely eliminated from the body within 72 h, with 46·3 and 50·2% of the dose being excreted in urine and faeces, respectively. Some portion of the metabolites was excreted in bile to enter into entero-hepatic cycling.

5. TAI-284 accounted for only a few per cent of the radioactivity in excreta. The major urinary and faecal metabolites were V, VI and III, while most of the biliary radioactivity was derived from metabolite VI.

6. After intravenous injection of [³H]TAI-284 to a pregnant rat radioactivity was transferred to foetuses.     

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.     

Metabolism of 6-Chloro-5-cyclohexylindane-1-carboxylic Acid (TAI-284), a New Non-steroidal Anti-inflammatory Agent. III. Species Differences in Metabolism

Abstract

1. After oral administration, the plasma concn. of TAI-284 reached a peak at 1 h (t_0·5 of 3·5 h) in mice, at 2 h (t_0·5 5 h) in rabbits and at 24 h (t_0·5 4·5 days) in guinea-pigs.

2. In mice and rabbits the major plasma metabolite was the pharmacologically active III (trans-4′-ol), but in guinea-pigs more than 97% of plasma radioactivity was accounted for by unchanged drug. Fraction II, containing an ulcerogenic metabolite, IIb (cis-3′-ol), was found in rat plasma but was not detected in the other 3 species.

3. In mice and rabbits, elimination of ingested radioactivity was completed in 72 h, while with guinea-pigs half the dose remained unexcreted at this time. In rats and mice, excretion in urine and faeces was almost equal, whereas in guinea-pigs and rabbits, more was excreted in urine than in faeces. The major urinary metabolites were the unidentified V and VI in rats and mice and metabolite III in guinea-pigs and rabbits.

4. Studies using liver homogenates or isolated liver profusion system demonstrated that limited hepatic entry of TAI-284 and lower enzyme activity were responsible for the slower metabolism in guinea-pigs.     

Biological Activity and Disposition of the Amphetamine Analogue 2-Aminopropylferrocene

1. 2-Aminopropylferrocene (FIPA) was rapidly absorbed following intraperitoneal administration to mice. From 5 to 120?min after administration, liver FIPA concn. remained constant while blood concn. declined steadily (t_0·5 = 114?min). In contrast, brain concn. of FIPA did not reach max until 30?min after administration, and then declined slowly (t_0·5 = 194?min). The apparent vol. of distribution of FIPA was 5·5 1/kg, and high affinity of FIPA for tissue was suggested by brain and liver concn. tenfold greater than blood concn.

2. Mice treated with FIPA (3-30?mg/kg) showed no differences in loco-motor activity from saline injected controls. However, at 100?mg/kg FIPA elicited convulsive behaviour in most mice.

3. In contrast to amphetamine, which markedly increased the spontaneous beating rate of isolated pargyline-treated rat atria, FIPA exhibited only a dose-dependent depressant effect on atrial rate.

4. Rats excreted 56-71% dose of ³H-FIPA in their urine in the first 96?h after dosing. Fractionation of urine indicated a large number of radioactive metabolites which were devoid of iron, but 32-43% of the FIPA administered was excreted unchanged. In contrast to ferrocene and amphetamine, which in rat are extensively hydroxylated, conjugated and excreted, no metabolites of FIPA containing an intact ferrocene moiety were detected.

5. In vitro, FIPA significantly inhibited metabolism of the cytochromt P-450 substrates aminopyrine and p-nitroamsole, but had no effect on the flavoprotein-mediated N-oxidation of N, N-dimethyloctylamine.     

Disposition of bemitradine,a Renal Vasodilator and Diuretic,in Man

1. ¹⁴C-Bemitradine (50 mg) was rapidly and efficiently absorbed (β89%) in man following a single oral dose, as a solution in gelatine capsules. Peak ¹⁴Clevels of 895 ± 154 ng equiv./ml (mean ± S.E.M.) were reached within 2h, and declined with half-lives of 1·07 ± 0·25 and 13·0± 5·6h.

2. No bemitradine was detected in plasma, but peak concn. (124±29ng/ml) of its desethyl metabolite were reached at 1·05±0·28h, and declined with a half-life of 1·32±0·08h.

3. Desethylbemitradine was rapidly metabolized to its ether glucuronide, a phenol and a dihydrodiol which were also present as glucuronide conjugates. The glucuronides were the major compounds in plasma from 2h after drug administration.

4. Excretion in 5 days amounted to 88·8±2·3% and 10·4±2·1% dose in urine and faeces respectively. No bemitradine or desethylbemitradine were excreted unchanged. 8-(2-Hydroxyethyl)-7-(3,4-dihydroxycyclohexa-l,5-dienyl)-l,2,4-triazolo-l,5c-pyrimidine-5-amine (E; 17% dose); 8-(2-hydroxyethyl)-7-(4-hydroxyphenyl)-l,2,4-triazolo-1.5c-pyrimidine-5-amine (F; 4% dose), their glucuronides (A, 19% dose and B, 6% dose respectively), desethylbemitradine glucuronide (D, 25% dose) and an unidentified metabolite (C, 12% dose) were excreted in urine. Compound F was the major faecal metabolite.     

Pharmacokinetics and pharmacodynamics of radio-labeled iloprost in elderly volunteers

Summary The plasma levels and excretion of tritium-labeled iloprost in healthy elderly male and female volunteers have been measured after i.v. infusion of 2 ng·kg⁻¹·min⁻¹ for 4 h and oral administration of 0.1 and 0.48 μg/kg. During infusion, a steady-state of labeled compounds in the plasma was not achieved. Total radioactivity declined from a mean of 408 pg equiv/ml in three phases, with half-lives of 24 min, 1.7 h and 5.0 h, respectively. A steady-state of unchanged iloprost was reached rapidly with a peak of 81 pg/ml. Plasma levels declined biphasically with half-lives of 6 min and 31 min. Total clearance was 24 ml· min⁻¹·kg⁻¹. Maximum concentrations of labeled substances after oral administration were 307 and 1,051 pg equiv/ml after 29 and 39 min respectively. The peak of unchanged iloprost (116 pg/ml) was observed 7.5 min after an oral dose of 0.48 μg/kg. Bioavailability was 16%. Iloprost was totally metabolized and the metabolities were mainly excreted in urine. The main biotransformation products in plasma and urine were tentatively identified by cochromatography as dinor-and tetranoriloprost and their glucuronides. ADP-induced platelet aggregation was reduce by 60% during the i.v. infusion and 15 min after oral administration of 0.48 μg/kg. Heart rate and blood pressure were virtually unaffected. Common side-effects were facial flush, headache and nausea.     

Absorption,metabolism and excretion of tamsulosin hydrochloride in man

1. The absorption, excretion and metabolism of tamsulosin hydrochloride (TMS), a potent α₁-adrenoceptor blocking agent, were studied in four healthy male subjects after a single oral administration of ¹⁴C-TMS at a dose of 0·2?mg.

2. Plasma and blood radioactivity concentrations attained peak levels (C_max) within 1?h after dosing and then declined biphasically. Mean terminal elimination half-lives were 11·8?h for plasma and 9·1?h for blood. The respective mean area under the radioactivity concentration-time curves (AUC_0-∞) were 122·8 and 57·8 ng equivalents h/ml.

3. Mean plasma C_max of unchanged TMS was 13·0 ng/ml. Plasma levels of TMS declined biphasically. Mean terminal elimination half-life and AUC_0-∞ were 8·4?h and 90·3 ng h/ml. The percentage of unchanged TMS to total radioactivity was 91% for C_max and 74% for AUC_0-∞ indicating small amounts of metabolites in plasma.

4. By 1 week post-dosing, 76·4% of the administered radioactivity was recovered in urine and 21·4% in faeces. The major part of radioactivity excreted in urine was recovered within the first 24?h (62·2% of the dose).

5. Unchanged TMS and 11 metabolites in 0-24-h urine samples were quantified. TMS accounted for 8·7% of the dose. Extensive excretion of the sulphate of the O-deethylated metabolite (M-1-Sul) and o-ethoxyphenoxy acetic acid (AM-1) was seen, accounting for 15·7 and 7·5% of the dose respectively.     

The metabolic fate of [3H]econazole in man

1. Following single oral doses of [³H]econazole base (500?mg) to two human subjects, excretion of radioactivity was prolonged, and incomplete after five days (means of 40% and 27% dose in urine and faeces respectively).

2. Plasma concn. of unchanged econazole and total radioactivity attained peak values at approx. the same time for each subject (1±5-3?h), but the former declined much faster than the latter. Most of the ³H in early plasma samples was present as unchanged drug and extractable metabolites, but after 24h concn. of econazole were close to the limit of detection (0±4μg/ml) and very little plasma ³H was extractable, whereas total³H concn. were still measurable after five days (mean 1±54μg/ml). Thus, plasma contained metabolites with much longer half-lives than econazole.

3. The main route of biotransformation of econazole in man involved multiple oxidation of the imidazole ring carbons followed by O-dealkylation and conjugation of the resulting alcohols, probably with glucuronic acid.     

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%).     

Metabolism of ethynodiol diacetate in the rhesus monkey before and after administration of rifampicin

1. On administration of a single oral dose of [4- ¹⁴C]ethynodiol diacetate (0·15 mg/kg) to rhesus monkey, plasma concn. of total ¹⁴C peaked after about 4 h. About 60% of the plasma radioactivity was present as glucuronide conjugates and no unchanged drug was detected.

2. Some 67 ±6% (mean ± S. D.) of the dose of ¹⁴C was excreted in 4 days, 50 ± 6% in urine and 18 ± 2% in faeces. Most of the urinary excretion occurred within 24 h of dosage.

3. Glucuronide conjugates accounted for 60% of the urinary ¹⁴C, and 46% of the faecal ¹⁴C was free steroids.

4. Norethisterone and its tetrahydro metabolites were identified in the free, glucuronide and sulphate fractions of plasma and urine. Keto-4,5-dihydronorethisterones and trihydroxy metabolites were identified in the conjugated fractions of urine, and a complex mixture of polar metabolites was detected in faeces.

5. Rifampicin treatment (7·5 mg/kg/day, orally) for 8 days decreased the half-life of total ¹⁴C in plasma following a single oral dose of 4-[¹⁴C]ethynodiol diacetate (0·15 mg/kg) from 44±4 to 24±2h.

6. Faecal elimination of total ¹⁴C was significantly increased to 29±5% of the dose following rifampicin treatment, but urinary excretion was unchanged.

7. Rifampicin treatment increased the amount of polar metabolites and decreased the amount of norethisterone in the free and conjugated fractions of plasma and urine. The amounts of sulphate and non-hydrolysed conjugates in faeces were increased after rifampicin treatment.     

The metabolic fate of [14C]oxaprotiline · HCl in man. I. Disposition and preliminary pharmacokinetics

1. Absorption, biotransformation and elimination of [¹⁴C]oxaprotiline · HCl have been studied after oral administration of 50 mg doses to two human subjects.

2. Absorption was complete, and peak blood concn. of total ¹⁴C were 590 and 297 ng equiv./ml after 3—6 h in the two subjects. After 11 days, 84 and 90% dose was excreted in urine, and a total of 98% was excreted.

3. Peak blood concn. of unchanged oxaprotiline were 16 and 19ng/ml before, and 167 and 207ng/ml after enzymic hydrolysis. The blood half-life in the two subjects was 23 and 29 h. The blood concn. of the desmethyl metabolite was low (2ng equiv./ml), but also increased after hydrolysis (11—19ng equiv./ml).

4. Oxaprotiline was bound (83%) in vitro to serum proteins. Sixty per cent was bound to serum albumin and 20% to α₁-acid glycoprotein.

5. In urine only 1% of total ¹⁴C was present as unchanged oxaprotiline, and 0.2% as the desmethyl metabolite. After enzymic hydrolysis these increased to 48 and 6%, respectively, and after acid hydrolysis to 85 and 10%.     

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.     

Identification of an N-Oxide as the Major Metabolite of the Analgesic O-(Diethylaminoethyl)-4-Chlorobenz-aldoxime Hydrochloride in Dogs

1. After oral administration to dogs of the analgesic O-(diethylaminoethyl)-4-chloro[7-¹⁴C]benzaldoxime hydrochloride together with piperazine hydro-chloride (2:1, w/w), at a dose of 4.5?mg/kg, the radioactivity was well absorbed and rapidly excreted. During 5 days, 81% of the dose (ca. 50% in 12?h) was excreted in urine and 10% in faeces.

2. Rates and routes of excretion of radioactivity were not altered in animals pre-treated with the drug for fourteen days.

3. Peak mean plasma concentrations of radioactivity (5.5 μg equiv./ml) occurred at 90 min after an oral dose and were higher than those at 2 min following an equivalent intravenous (3.4 μg equiv. /ml) or rectal (4.0 μg equiv. /ml) dose which gave a max. at 45?min.

4. The drug was rapidly and extensively metabolized and no unchanged drug was detected in the plasma or urine. The major urinary metabolite was the N-oxide of the parent compound accounting for 34% and 23% dose excreted in the urine of males and females respectively during 12?h after administration.     

Studies related to the metabolism of anabolic steroids in the horse: testosterone

1. After intramuscular administration of [4-¹⁴C]testosterone to two cross-bred gelded horses, 45% of the radioactivity was excreted in urine in 96 h. Small amounts of urinary activity could still be detected at 200 h.

2. Neutral metabolites obtained after both enzyme and acid hydrolysis of urine samples have been investigated by g.l.c.-mass spectrometry.

3. 5α-Androstane-3β, 17α-diol was found only in the enzyme-hydrolysable extract and testosterone only in the acid-hydrolysable extract. 5α-Androstane-3β, 17β-diol and 3β-hydroxy-5α-androstan-17-one were found predominantly in the acid-hydrolysable extract.     

The metabolic fate of tizoprolique acid in baboons

1. After oral administration of the anti-lipolytic drug [¹⁴C]tizoprolique acid (2-propyl-5-carboxy1[4-¹⁴C]thiazole), to baboons (60?mg/kg), the radioactivity was well absorbed and rapidly excreted. During 6 and 24?h respectively, 60±25% (S.D.) and 90±2% were excreted in the urine.

2. Plasmaconcn. of ¹⁴C reached a max. (182±65, range 85–221 ±g equiv./ml) at 1–1.5?h after an oral dose, and declined rapidly with an apparent half-life of about 0.5?h. A mean of 77±7% of the ¹⁴C in peak plasma samples was bound to plasma proteins, somewhat less than that of [¹⁴C]tizoprolique acid (84±5%).

3. Tissue concn. of ¹⁴C were highest in an animal killed at 0.5?h after an oral dose, but were lower than those in plasma in all tissues examined except the kidneys.

4. The major metabolite of tizoprolique acid was its glycine conjugate, which accounted for about 80% dose excreted in the 24h urine. About 2% dose was excreted as unchanged drug. About 70% and 20% respectively of plasma ¹⁴C were associated with the unchanged drug and its glycine conjugate during the period 15?min to 4h after dosing.     

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.     

Pharmacokinetics,distribution, metabolism,and excretion of the dual reuptake inhibitor [14C]-nefopam in rats

1.?This study examined the pharmacokinetics, distribution, metabolism, and excretion of [¹⁴C] nefopam in rats after a single oral administration. Blood, plasma, and excreta were analyzed for total radioactivity, nefopam, and metabolites. Metabolites were profiled and identified. Radioactivity distribution was determined by quantitative whole-body autoradiography.

2.?The pharmacokinetic profiles of total radioactivity and nefopam were similar in male and female rats. Radioactivity partitioned approximately equally between plasma and red blood cells. A majority of the radioactivity was excreted in urine within 24?hours and mass balance was achieved within 7 days.

3.?Intact nefopam was a minor component in plasma and excreta. Numerous metabolites were identified in plasma and urine generated by multiple pathways including: hydroxylation/oxidation metabolites (M11, M22a and M22b, M16, M20), some of which were further glucuronidated (M6a to M6c, M7a to M7c, M8a and M8b, M3a to M3d); N-demethylation of nefopam to metabolite M21, which additionally undergoes single or multiple hydroxylations or sulfation (M9, M14, M23), with some of the hydroxylated metabolites further glucuronidated (M2a to M2d).

4.?Total radioactivity rapidly distributed with highest concentrations found in the urinary bladder, stomach, liver, kidney medulla, small intestine, uveal tract, and kidney cortex without significant accumulation or persistence. Radioactivity reversibly associated with melanin-containing tissues.     

Absorption,distribution and excretion of the anti‐tuberculosis drug delamanid in rats: Extensive tissue distribution suggests potential therapeutic value for extrapulmonary tuberculosis

Delamanid (OPC‐67683, Deltyba™, nitro‐dihydro‐imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug‐resistant tuberculosis. The absorption, distribution and excretion of delamanid‐derived radioactivity were investigated after a single oral administration of ¹⁴C–delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 h post‐dose, and thereafter decreased slowly. Radioactivity levels were 3‐ to 5‐fold higher in lung tissue at time to maximum concentration compared with plasma. In addition, radioactivity was broadly distributed in various tissues, including the central nervous system, eyeball, placenta and fetus, indicating that ¹⁴C–delamanid permeated the brain, retinal and placental blood barriers. By 168 h post‐dose, radioactivity in almost all the tissues was higher than that in the plasma. Radioactivity was also transferred into the milk of lactating rats. Approximately 6% and 92% of radioactivity was excreted in the urine and feces, respectively, indicating that the absorbed radioactivity was primarily excreted via the biliary route. No significant differences in the absorption, distribution and excretion of ¹⁴C–delamanid were observed between male and female rats. The pharmacokinetic results suggested that delamanid was broadly distributed to the lungs and various tissues for a prolonged duration of time at concentrations expected to effectively target tuberculosis bacteria. These data indicate that delamanid, in addition to its previously demonstrated efficacy in pulmonary tuberculosis, might be an effective therapeutic approach to treating extrapulmonary tuberculosis. Copyright © 2017 John Wiley & Sons, Ltd.     

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

Abstract

1. The metabolism of (±)-[¹⁴C]adrenaline has been studied in two horses after intravenous administration.

2. The plasma half-life of ¹⁴C was 228 min (Horse A) and 100 min (Horse B).

3. Excretion of ¹⁴C in the urine in 20 h was 90% (A) and 70% (B). Over 94% of the excreted radioactivity has been identified.

4. The two horses differed in their metabolism of adrenaline. Unchanged drug accounted for 11% (A) and 20% (B), and for A and B respectively, metabolites excreted were 3-methoxyadrenaline (10%, 21%), 4-hydroxy-3-methoxymandelic acid (16%, 13%), 3,4-dihydroxyphenylglycol (6%, 0%), 4-hydroxy-3-methoxyphenylglycol (10%, 3%), 3,4-dihydroxybenzoic acid (5%, 0%), 3,4-dihydroxymandelic acid (7%, 3%) and 4-hydroxy-3-methoxybenzoic acid (18%, 4%).