The Metabolism of Talampicillin in Rat,Dog and Man

1. After administration of [phthalidyl-¹⁴]talampicillin (Talpen® to rat. dog and man, radioactivity was excreted mainly in the urine (90%, 86% and 98% in rat, dog and man respectively).

2. After administration of [ampicillin-¹⁴C]talampicillin, radioactivity was excreted in the urine of rats and dogs to a lesser extent (35% in both species) and only a small proportion of the dose was excreted in the bile (6% in rats, less than 0·1% in dogs).

3. The pattern of radiometaboletes was very similar in extracts of the urines of rat, dog and man dosed orally with [phthalidyl-14C]talampicillin. The major metabolite was 2-hydroxymethylbenzoic acid.

4. Unchanged talampicillin was present in the hepatic portal vein blood of dog and thus reached the liver, whereas in rat, no parent compound could be detected in portal vein blood. This result may help to explain differences in toxicity of the compound in rat and dog.

5. Studies in vitro showed that the intestinal wall is an important site of hydrolysis of talampicillin in rat and dog.     

The Metabolism of 5-(4-Acetamidophenyl)Pyrazin-2(1H)-One in Rat,Dog and Cynomolgus Monkey

1. The metabolism and disposition of ¹⁴C-acetamidophenyl pyrazinone has been studied in rat, dog and cynomolgus monkey. The compound was well absorbed and rapidly excreted in urine and faeces by all three species.

2. Distribution of ¹⁴C-pyrazinone was rapid and extensive with the exception of the central nervous system where concentrations were at, or below, the limit of detection.

3. Whereas, in in vitro studies, metabolites (but not the parent compound) weakly inhibited some activities of the cytochrome P-450 system, there was evidence from in vivo studies in the rat that the compound and/or its metabolite(s) are weak selective inducers of cytochrome P-450.

4. Metabolite patterns were similar in all three species. The major route of metabolism was glucuronidation at the oxygen of the pyrazinone ring. Other metabolites originated from metabolism by gut microflora with subsequent hepatic metabolism.     

The Fate of Phenglutarimide Hydrochloride in the Rat and Man

Abstract

1. In the rat, [¹⁴C]phenglutarimide HCl was completely absorbed from the gastrointestinal tract and totally excreted in the urine within 24 h after dosing. The drug was not metabolized.

2. [¹⁴C]Phenglutarimide was widely distributed throughout the body of the rat but only very low levels of radioactivity were detected in the brain. In pregnant animals the drug traversed the placenta and radioactivity was detected in the foetus and amniotic fluid in concentrations higher than or similar to those in the maternal plasma.

3. On absorption from the gastrointestinal tract, the drug was rapidly excreted into the urine and consequently tissue levels were low.

4. In man, after oral administration of non-radioactive phenglutarimide, the drug was excreted completely in the urine as the unchanged compound within 24 h after dosing.

5. In mice, phenglutarimide inhibited the peripheral but not the central actions of oxotremorine, an observation in accord with the distribution pattern of the drug in the rat.

6. Phenglutarimide inhibited the response of the isolated guinea-pig bladder to coaxial stimulation. It is suggested that sufficiently high concentrations of phenglutarimide may be reached in the bladder in vivo to inhibit the bladder reflex in man.     

Metabolism of Debrisoquine Sulphate in Rat,Dog and Man

1. The metabolism of debrisoquine sulphate in the dog has been studied and is similar to that in rat and man.

2. Two acidic urinary metabolites, shown to be present in rat, dog and man, have been isolated from rat urine. After derivatization they were characterized by n.m.r. and mass spectroscopy as methyl 2-[2-(4,6-dimethylpyrimidylamino)-methyl]-phenylacetate and 2-[2-(4,6-dimethylpyrimidylamino)-ethyl]benzoate.     

The Fate of an Experimental MAO Inhibitor,N-Cyclopropyl-2-Chlorophenoxyethylamine (Lilly 51641) in the Rat and in Man

Abstract

1. In vivo metabolism studies have shown N-cyclopropyl-2-chlorophenoxy-ethylamine (Lilly 51641) to be extensively metabolized in the rat. Those metabolites identified include 2-chlorophenoxyacetic acid, N-cyclopropyl-4-hydroxy-2-chlorophenoxyethylamine and 4-hydroxy-2-chlorophenoxyethanol, together with a number of minor products. The major route of elimination of these metabolites is through the kidney.

2. The major in vitro metabolites of Lilly 51641 have been identified as 2-chlorophenoxyethylamine, 2-chlorophenoxyacetaldehyde, 2-chlorophenoxyacetic acid and 2-chlorophenoxyethanol. It thus appears that this drug is metabolized by the following sequence: N-dealkylation, deamination and aldehyde oxidation or reduction.

3. Aromatic hydroxylation was found to be an independent but important mechanism involved in the metabolism of Lilly 51641.

4. Human urinary metabolites of Lilly 51641 were separated and identified. The nature of these metabolites indicated that the same mechanisms of detoxication were involved in the biotransformation in the human as were involved in the rat.

5. The major human urinary metabolite was 4-hydroxy-2-chlorophenoxy-acetic acid.     

Metabolism of 2-Benzylthio-5-Trifluoromethyl Benzoic Acid (BTBA) by the Rat,Dog and Man

Abstract

1. Benzylthio-5-trifluoromethylbenzoic acid (BTBA) is well absorbed by rat, dog and man. The time course of disappearance from plasma in all three species suggests enterohepatic circulation.

2. The principal excretion product in rat urine has been identified as 2-mercapto-5-trifluoromethylbenzoic acid arising via S-dealkylation.

3. 2-Mercapto-5-trifluoromethylbenzoic acid is also converted to the disulphide metabolite, [2,2′-dithiobis(5-trifluoromethyl)benzoic acid], which is secreted together with BTBA and their glucuronide conjugates in rat bile. Rapid hydrolysis in the intestine results in faecal elimination of largely free BTBA and disulphide metabolite (2,2′-dithiobis[5-trifluoromethyl]benzoic acid).

4. In man, approximately 50% of the dose is recovered from urine as amino-acid and glucuronide conjugates of the drug and its debenzyl metabolite (2-mercapto-5-trifluoromethylbenzoic acid).

5. The drug is not readily metabolized by the dog and is secreted with bile and eliminated unchanged with faeces.     

Excretion and Biotransformation of Carboxymethyl-cysteine in Rat,Dog, Monkey and Man

1. Following an oral dose of S-carboxymethyl[³⁵S]cysteine, monkey (rhesus and African green), rat, dog, and man excreted 77, 88, 95, and 100% respectively of the ³⁵S radioactivity in urine and 7·0, 2·5, 0·7, and 0·3% in faeces during a 3 to 4 day period.

2. The principal drug-related components excreted were unchanged carboxymethylcysteine, dicarboxymethyl sulphide and inorganic sulphate.

3. Rat, dog, and man excreted primarily dicarboxymethyl sulphide and unchanged carboxymethylcysteine and no inorganic sulphate (rat, 7%).

4. Monkey excreted largely inorganic sulphate, moderate amounts of dicarboxymethyl sulphide and a trace of unchanged drug.     

Plasma Protein Binding of the Experimental Antitumour Agent Acridine-4-carboxamide in Man,Dog, Rat and Rabbit

Abstract— The plasma binding of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC) was investigated in-vitro by equilibrium dialysis for 3 h at 37°C against isotonic phosphate buffer (pH 7·35) using [³H]AC. There were significant species differences with the smallest % free fraction (mean ± s.d.) occurring in human plasma (3·4 ± 0·2), followed by dog (8·1 ±0·4), mouse (14·8 ± 0·8), rat (16·3 ± 0·9) and rabbit (20·2 ± 0·7). In plasma from healthy individuals (n = 5), the % free fraction ranged from 2·7 to 3·8. In physiological solutions of human proteins, the greatest binding was observed for α-acid glycoprotein (AAG) (0·75 g L^?1) with a mean free fraction of 24·1 ± 2·2%, followed by albumin (40 g L^?1) with 31·6 ± 0·7 and 39·8 ± 2·5% for fatty-acid-free and globulin-free, respectively. There was also some binding to globulins (5 g L^?1) with a mean % free fraction of 70·3 ± 1·6 and 84·8 ± 2·2 for Conn's fraction I and IV, respectively. Binding data from the displacement of [³H]AC by increasing concentrations of AC in human AAG (0·75 g L^?1) or albumin solution (40 g L^?1) indicated that AAG had 10-fold greater binding affinity for AC (K_a, 7·8 × 10⁴ m^?1) compared with albumin (K_a, 6·8 × 10³ m^?1). In human plasma enriched with AAG there was a significant negative linear correlation (r = 0·932; P < 0·001) between % AC free fraction and increasing AAG concentration over the range 0·6–4·5 g L^?1. Small but significant (P < 0·05) increases in AC free fraction occurred in the presence of various metabolites (50 and 100 μm) but, of those tested, only N-monomethyl-acridine carboxamide increased the free fraction to the same extent as parent AC.     

维生素B1催化合成1-(3-甲氧基-4-丙氧基-5-硝基苯基)-4-(3,4,5-三甲氧基苯基)-1,4-二酮

研究以NaCN和维生素B1为催化剂合成MK-287的关键中间体1-(3-甲氧基-4-丙氧基-5-硝基苯基)-4-(3，4，5-三甲氧基苯基)-1，4-二酮（1）的催化效果。结果表明：维生素B1较文献报道的催化剂ETB具有反应时间短、成本低廉的优点，可代替ETB合成目的化合物。     

Metabolic Fate of N-n-Butyl-N-(4-hydroxybutyl)-nitrosamine and its Analogues: Selective Induction of Urinary Bladder Tumours in the Rat

1. The metabolic fates of N-n-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and N, N-di-n-butylnitrosamine (DBN) were investigated in the rat and other animal species, to elucidate a possible relationship between metabolism and organotropic carcinogencity to the urinary bladder of these N-nitrosamines.

2. The principal urinary metabolite of BBN as well as of DBN in the rat was N-n-butyl-N-(3-carboxypropyl)nitrosamine (BCPN), which was demonstrated to be the active form of these compounds as bladder carcinogen. The species difference in response to BBN or DBN is discussed on the basis of the urinary excretion rate of BCPN.

3. Metabolism in vivo and carcinogenicity of a number of BBN analogues were investigated in the rat and a general scheme for biotransformation of N-alkyl-N-(hydroxyalkyl)nitrosamines is given.

4. A possible correlation of structure and metabolism with organotropic carcinogenicity of BBN analogues is discussed, with special reference to selective induction of bladder tumours.

5. A clear demonstration of overlapping carcinogenic and mutagenic activities is presented for BBN, DBN and related compounds.     

维生素B1催化合成1-(3-甲氧基-4-丙氧基-5-硝基苯基)-4-(3,4,5-三甲氧基苯基)-1,4-二酮

研究以NaCN和维生素B1为催化剂合成MK-287的关键中间体1-(3-甲氧基-4-丙氧基-5-硝基苯基)-4-(3,4,5-三甲氧基苯基)-1,4-二酮(1)的催化效果.结果表明维生素B1较文献报道的催化剂ETB具有反应时间短、成本低廉的优点,可代替ETB合成目的化合物.     

Disposition and Metabolic Fate of Tiaramide Hydrochloride,a New Anti-inflammatory Agent,in the Rat

1. A new non-steroidal anti-inflammatory agent, 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)[¹⁴C]acetyl]- 1-piperazine-ethanol hydrochloride (tiaramide hydrochloride) was rapidly absorbed after oral administration, reaching peak serum concn. in 20 min, with a half-life of 2·7 h. After intravenous injection the concn. of tiaramide decreased biphasically with half-lives of 0·2 and 1·3 h.

2. The metabolism of tiaramide, both in vivo and in vitro with rat liver 10 000 g supernatant fraction, gave three major metabolites identified as 1-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-piperazine (DETR), 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazineacetic acid (TRAA), and 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazineethanol 1-oxide (TRNO). The major serum metabolites were TRAA and TRNO.

3. After oral administration, unchanged tiaramide was found in high concn. in liver, kidney and lung. Tissue levels of tiaramide were 4–6 times higher than serum. Distribution of tiaramide in inflammatory tissue was also demonstrated. The major tissue metabolite was DETR and its concn. was 20–40 times higher in tissue than in serum.

4. Urinary excretion was almost complete within 24?h after oral administration. The major urinary metabolites were TRAA and TRNO.

5. Repeated administration of tiaramide did not alter the metabolism of tiarsmide.     

Gastric cytoprotective, antisecretory and antiulcer activities of (E)-4-oxo-4-(3,4,5-trimethoxyphenyl)-2-butenoic acid (RU 38086)

As a result of trials of a large series of compounds, RU 38086 (E)-4-oxo-4-(3,4,5-trimethoxyphenyl)-2-butenoic acid) was selected because of its cytoprotective, antisecretory and antiulcer properties. In pylorus-ligated rats, RU 38086 dose-dependently decreased the total acid output, at 2.5, 5 and 10 mg/kg orally and at 10 and 50 mg/kg intraduodenally. In the perfused rat stomach, 1.2 mg/kg RU 38086 in situ inhibited acid secretion stimulated by histamine or pentagastrin but was inactive against carbachol. In the same test 5 mg/kg intravenously did not antagonize pentagastrin-induced acid secretion. In the cat Heidenhain pouch, 0.6 mg/kg RU 38086 was also antisecretory, reducing the acid concentration when in contact with the mucosa of the pouch. In ulcers induced in rats by ligature of the pylorus plus acetylsalicylic acid, RU 38086 at 2.5 and 5 mg/kg demonstrated much more striking activity after oral than after intraduodenal administration. It also had antiulcer activity against stress ulcers (restraint plus cold), starting at a dose of 5 mg/kg orally. RU 38086 had marked gastric cytoprotective activity in rats against the necrotizing effects of ethanol from the low dose of 0.3 mg/kg orally. This cytoprotective activity was not significantly affected by indomethacin pre-treatment. At 4 and 20 mg/kg orally, RU 38086 strongly increased prostaglandin E2 levels in gastric juice of pylorus-ligated rats and in stomach tissue of normal rats. These data indicate that RU 38086 is an orally effective cytoprotective, antisecretory and antiulcer agent.     

The Metabolism of the Local Anaesthetic Fomocaine (1-Morpholino-3-[p-phenoxymethylpheny1]propane) in the Rat and Dog after Oral Application

1. The metabolism of fomocaine following its oral administration to male and female Wistar rats and male beagle dogs has been qualitatively investigated.

2. The drug is metabolized in both species by aromatic hydroxylation, N-oxidation, splitting of the ether link and, in the dog, by removal of the morpholine group.

3. The rat and dog excrete some unchanged fomocaine in the urine together with p-hydroxyfomocaine (free and conjugated), fomocaine-N-oxide, p-hydroxy-fomocaine-N-oxide and p-(γ-morpholinopropyl)benzoic acid. In addition, the dog excretes morpholine in the urine.     

The Effect of Route of Administration on the Metabolic Fate of Terbutaline in the Rat

Abstract

1. The metabolic fate of [³H]terbutaline has been investigated in rats after oral, subcutaneous, intraperitoneal and intraportal administration (5 mg per kg).

2. About half the administered radioactivity was excreted in the urine and the remainder in faeces regardless of route of administration. Urinary excretion was essentially complete in 24 h, but an additional 10% of the dose was excreted in the 24–48 h faeces.

3. Only one metabolite, a glucuronide conjugate of terbutaline, was excreted in the urine along with unchanged drug. About 3% of the dose was excreted unchanged in urine following oral administration. Ratios of terbutaline glucuronide to free drug were 1 : 1, 2 : 1 and 13 : 1 after subcutaneous, intraperitoneal or intraportal, and oral administration respectively, suggesting that the orally administered drug is extensively conjugated in the intestinal mucosa.

4. Measurement of the mobility-pH profile by high-voltage paper electrophoresis was utilized to characterize the conjugate.     

Effects of KB-5492, 1-(3,4,5-trimethoxybenzyl)-4-((4-methoxyphenyl)oxycarbonylmethyl) p iperazine monofumarate monohydrate, on gastric lesions and gastric secretion in rats

Effects of a newly synthesized compound, KB-5492, on gastric lesions and gastric secretion were studied in rats. Oral KB-5492 inhibited the lesions induced by HCl.ethanol, HCl.aspirin, water-immersion stress, indomethacin, histamine and prednisolone at 30-300 mg/kg. The ED50 values varied from about 35 to 98 mg/kg. KB-5492 had no effect on gastric acid secretion even at 300 mg/kg. KB-5492 appeared to have a much more potent protective effect than a known anti-ulcer drug, sofalcone, against acute gastric lesions.