The biotransformation of [14C]lormetazepam in dogs,rabbits, rats and rhesus monkeys

1. After oral or intravenous doses (0.25?mg/kg) of [¹⁴C]lormetazepam to rats, most of the urinary radioactivity was associated with polar components and < 1% dose was excreted as unconjugated lormetazepam. About 30% of an oral dose was excreted in rat bile as a conjugate of lormetazepam and about 50% dose as polar metabolites. Plasma also contained mainly polar metabolites, and unchanged lormetazepam represented at most 10% of total plasma radioactivity after an oral dose.

2. Almost all the radioactivity in dog, rhesus monkey and rabbit urine, after oral or intravenous doses (0.5–0.7?mg/kg) of [¹⁴C]lormetazepam, was associated with conjugated material. In the dog there were only two major components, conjugates of lormetazepam and lorazepam (N-desmethyl-lormetazepam) which accounted for about 24% and 14% respectively of the oral dose in the 0–24?h urine. The same two conjugated components were also present in dog bile. Conjugated lormetazepam was the only major component in monkey and rabbit urine and accounted for about 60% dose in the 0–24?h urine of each species, while conjugated lorazepam accounted for only about 0.5% and 4% respectively.

3. Dog and monkey plasma contained mostly conjugated material after oral and intravenous doses (0.05–0.07?mg/kg of [¹⁴C]lormetazepam. Dog plasma after an oral dose contained conjugates of both lormetazepam and lorazepam with peak concn. at 1?h of 130 and 47 ng/ml respectively. Concn. of these conjugates in plasma declined with apparent terminal half-lives of about 17 and 27?h respectively after oral doses, and 13?h in both cases after intravenous doses. Conjugated lormetazepam was the only major component in monkey plasma representing a peak concn. of 180 ng/ml at 1?h after an oral dose, and declined with an apparent terminal half-life of about 11?h after oral or intravenous doses.

4. Lormetazepam crosses the placental ‘barrier’ of rabbits: its concn. in the foetus were similar to those in maternal plasma after intravenous doses.     

The metabolic fate of Sormodren (bornaprine hydrochloride) in animals and humans

1. Single oral doses of the anticholinergic drug [¹⁴C]Sormodren to rats (1?mg/kg), dogs (0.3?mg/kg) and humans (0.03?mg/kg) were well absorbed. Excreted in urine and faeces were means of 31 and 70%, 53 and 39%, and 78 and 4% in rats, dogs, and humans, respectively, during five days: excretion was prolonged and still incomplete at five days in humans.

2. Peak plasma levels of ¹⁴C (scaled for dose) were generally reached within 1–2h after oral doses in rats, 49 (ng/ml)/(mg/kg), dogs 290 (ng/ml)/(mg/kg) and humans 410(ng/ml)/(mg/kg), and declined with half-lives of approx. 5, 12 and 30?h, in these species respectively. Repeated oral doses of [¹⁴C]Sormodren to dogs resulted in some accumulation of ¹⁴C in the plasma.

3. Tissue concn. of ¹⁴C in dogs were generally higher than those in rats, particularly in the brain, lungs and eyes. The tissue distribution of ¹⁴C in rats and dogs was consistent with that of a compound readily eliminated by both renal and hepatic routes.

4. Basic metabolites in dog and human, urine and plasma were investigated using a combination of?h.p.l.c. and g.l.c.-mass spectrometry. Unchanged Sormodren was not detected in the dog samples and was only a minor component in human urine and plasma. Some metabolites were present as conjugates.

5. A basic extract of enzyme-hydrolysed dog urine (5?mg/kg dose) contained 42% of the urine ¹⁴C. The major metabolites in this fraction were identified as three isomers of monohydroxy-N-desethyl-Sormodren and three isomers of monohydroxy-Sormodren, resulting from hydroxylation in the bicyclic ring. The positions of oxidation were not determined. A similar extract from dog urine (0.3?mg/kg dose) contained 26% of the urine ¹⁴C and the major metabolites were identified as isomers of monohydroxy-N-desethyl-Sormodren.

6. A basic extract of enzyme-hydrolysed human urine (0.03?mg/kg dose) contained 23% of the urine ¹⁴C. The unchanged drug was only a minor component and most of the radioactivity was associated with five isomers of monohydroxy-Sormodren, hydroxylation having occurred in the bicyclic ring.

7. Basic extracts of dog and human plasma only contained about 10% of the plasma ¹⁴C. Metabolites were chromatographically similar to the hydroxylated metabolites identified in the corresponding urine samples.     

Pharmacokinetic studies on nicardipine hydrochloride,a new vasodilator,after repeated administration to rats,dogs and humans

1. Various doses of [¹⁴C]nicardipine HCI were administered orally at different intervals for different periods to rats and dogs, and cumulative excretion, plasma concn. of unchanged drug, plasma clearance, tissue distribution, and AUC determined.

2. Plasma concn. in 12 patients with cerebrovascular disease receiving 20?mg three times per day for 28 (6 patients) or 365 days (6 patients) was determined on various days 1?h after the third dose.

3. In tissues of rats receiving 3?mg/kg/day for 21 days, distribution 1h after administration on day 14 was 1.4–2.5 times higher than on day one; there was no statistical difference between day 14 and 21, suggesting that a steady state had been established within 14 days.

4. In rats receiving 3?mg/kg/day for seven days, cumulative excretion was 97.3% administered drug, indicating no tendency to accumulation.

5. Doses of 10?mg/kg three times at 3?h intervals to dogs significantly increased the plasma concn. on repeated administration, but this was not the case if the drug was administered at 6?h intervals or if the dose was decreased to 2?mg/kg. These non-linear pharmacokinetics may be ascribable to saturation of the hepatic drug-metabolizing enzyme activity.

6. In dogs given 5?mg/kg three times per day at 3?h intervals for seven days, max. plasma concn. and AUC on day 4 were 1.8 and 1.6 times higher, respectively, than on day 1. On days 4 and 7, these values were similar, suggesting that a steady state had been established within 4 days.

7. In six patients receiving the drug for 28 days, the mean plasma concn. on day 1, 7, 14, and 28 was approx. 0.1 μg/ml, similar to the value on day 365 in the other six patients. This indicates that during long periods of administration, the plasma concn. of the drug shows no tendency to increase.     

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.     

The distribution,excretion and biotransformation of p-dichloro[14C]benzene in rats after repeated inhalation,oral and subcutaneous doses

1. Following repeated daily whole-body exposure (3h/day) of rats to atmospheres containing p-dichloro[¹⁴C]benzene (1000p.p.m.), or administration of oral or subcutaneous doses (250?mg/kg/day), 24-h tissue concn. of ¹⁴C were similar and did not increase after six days dosing, but tended to decrease.

2. After repeated daily atmospheric exposures or oral doses, highest concn. of ¹⁴C occurred in fat, kidneys, liver and lungs. Concn. declined rapidly to near or below limits of detection (< 0.2 p.p.m.) in plasma and tissues at 5 days. After similar subcutaneous doses, tissue concn. declined more slowly.

3. During five days after repeated dosing, most excreted ¹⁴C(91–97%) was in the urine. Little was excreted in faeces or expired air. Excretion was more prolonged following subcutaneous administration. After single doses to bile duct-cannulated animals, 46–63% of the excreted ¹⁴C was in the bile during 24h.

4. The pattern of metabolites in urine and bile was similar after each route of administration although there were quantitative differences. Urine extracts contained two major ¹⁴C-components, namely a sulphate and a glucuronide of 2,5-dichlorophenol, representing 46–54% and 31–34% of the urinary ¹⁴C respectively. Two minor components were identified by mass spectrometry as a dihydroxydichlorobenzene and a mercapturic acid of p-dichlorobenzene.

5. The glucuronide of 2,5-dichlorophenol was the major ¹⁴C component in bile (30–42%).     

Species differences in the disposition and metabolism of camazepam

1. After i.v. injection of camazepam, plasma camazepan concn. declined biexponentially. The half-life of the elimination phase (t_{1/2, β}) increased in the order: mice (0.73?h), rats (1.3?h), dogs (5.3?h).

2. After oral dosing of camazepam, absorption was almost complete whereas systemic availability varied eight-fold, i.e., rats and mice (10.15%) < dogs and monkeys (about 60%) < humans (> 90%), indicating species difference in the first-pass effect.

3. Camazepam was metabolized extensively in all species investigated to more than 10 metabolites, which were desmethyl, descarbamoyl and/or hydroxy products.

4. In comparison with camazepam, plasma concn. of pharmacologically active metabolites, temazepam, oxazepan and hydroxy camazepam, were much higher in rats and mice than in dogs and monkeys.     

The metabolism of the anti-inflammatory drug eterylate in rat,dog and man

1. Oral doses of ¹⁴C-eterylate were well absorbed by rat and man and excreted mainly in the urine (94% dose by rat in three days and 91% by man in five days). Oral doses to dogs were excreted in similar proportions in both the urine and faeces, although faecal ¹⁴C was probably derived in part, from biliary-excreted material.

2. Peak plasma ¹⁴C and drug concn. were generally reached between one and three hours after oral doses. In humans, only two metabolites, salicylic acid and 4-acetamido-phenoxyacetic acid, were detected in plasma. The latter was cleared more rapidly than the former and hence plasma salicylate concn. reached a peak (10.9 and 19.8 μg/ml in Subjects 1 and 2, respectively) and initially declined with a half-life of about two-three hours. Plasma 4-acetamidophenoxyacetic acid concn. reached a peak (4.3, 10.0 μg/ml, respectively) and declined with a half-life of about one hour.

3. Tissue concn. of ¹⁴C were generally greater in dogs than in rats. Highest conc. occurred at three hours in dogs and at one hour in rats. Apart from those in the liver and kidneys, tissue concoccurred were lower than those in the corresponding plasma.

4. Unchanged drug was not detected in urine or plasma of any species and was rapidly metabolized in human plasma. The major ¹⁴C components in human urine were identified as salicyluric acid and 4-acetamidophenoxyacetic acid; minor metabolites were salicylic acid, gentisic acid and paracetamol. These metabolites were also detected in rat urine albeit in different proportions to those in human urine. Dog urine contained less of these metabolites and a major proportion of the ¹⁴C was associated with relatively non-polar components. Although salicylic acid and 4-acetamidophenoxyacetic acid were the only major circulating metabolites in man and rat, dog plasma also contained the non-polar urine metabolites.     

The Metabolism and Disposition of 14C-Indolidan,a Potent and Orally Active Cardiotonic Agent,in Four Species of Laboratory Animals

1. The metabolism and disposition of ¹⁴C-indolidan, a potent, orally-active positive inotrope with vasodilator properties, has been studied after single dose oral administration to rats, mice, dogs and monkeys.

2. Excretion of ¹⁴C in all 4 species was mostly via the urine, largely as parent drug together with two other major metabolites.

3. The two metabolites have been isolated and identified, by mass spectroscopy and ¹H-n.m.r., as a dehydro-compound, with a double bond in the pyridazanone ring, and a hydroxylated derivative of the parent drug.

4. Plasma t_1/2 values, based on ¹⁴C, were 14 h in dog, 5 h in mouse and 8 h in monkey. Plasma t_1/2 of parent drug, by h.p.l.c. was 10 h in dog, approx. 5h in rodents, and 8h in monkeys.

5. Tissue distribution in rats showed no accumulation in any tissue; ¹⁴C concn. in all tissues were indistinguishable from background 48 h after dosage. ¹⁴C peaked at 6–8 h for most tissues but in blood and plasma, ¹⁴C was maximal 1 h after dosing.     

Disposition of a new tetrahydrocarbazole analgesic drug in laboratory animals and man

1. The disposition of AY-30,068 (I), a new tetrahydrocarbazole analgesic drug, was studied in mice, rats, dogs, rhesus monkeys, and man.

2. Oral doses of the ¹⁴C-labelled drug in aqueous solution were well absorbed in rodents, but absorption of oral doses of the crystalline drug in dogs was poor. Due to the virtual absence of serum metabolites in rats and dogs, the bioavailability of I was nearly identical to the extent of absorption. Although a small first-pass effect was observed in mice, unchanged I represented a major portion of serum radioactivity.

3. A linear increase in the serum concentrations of I occurred at doses between 0.05 and 25?mg/kg in rats, 0.1 and 50?mg/kg in dogs, and 1–160?mg in man. In rhesus monkeys given a 0.5?mg/kg oral dose, the C_max and AUC of I were similar to values obtained following a corresponding dose in dogs.

4. After i.v. administration of a 1.0?mg/kg dose the terminal elimination half-life (t1/2β) of I was 4?h in mice and 9–10h in rats and dogs. In rodents, dogs, and several human subjects, the elimination of I was interrupted by secondary peaks. Enterohepatic circulation was confirmed in bile duct cannulated rats, where the t1/2β of I was decreased to 2.4?h. In rodents the serum clearance and apparent volume of distribution of I were 0.04–0.21/kg.?h and 0.5–0.81/kg, respectively, and 0.61/kg.h and 9.81/kg in dogs.

5. In rodents and dogs dosed with ¹⁴C-labelled I, radioactivity was excreted almost entirely in the faeces. No unchanged I was detected in rat bile, while about 70% of the radioactivity corresponded to conjugates of parent drug.     

Species Differences in Metabolism of Tiaramide Hydrochloride,a New Anti-inflammatory Agent

1. Urinary excretion of the radioactivity in 24?h after oral administration of [¹⁴C]tiaramide hydrochloride was 67% of the dose in mice, 59% in rats, 41% in dogs and 74% in monkeys.

2. The serum half-lives of tiaramide after intravenous administration were approximately 0·2?h in mice, 0·8?h in rats and 0·5?h in dogs.

3. Marked species variations were noted in the composition of metabolites in the serum and urinary radioactivity. The major metabolites found were 1-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-piperazine (DETR) and 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazineacetic acid (TRAA) in mice, TRAA and 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-pipera-zineethanol 1-oxide (TRNO) in rats, TRNO and tiaramide-O-glucuronide (TR-O-Glu) in dogs, and TRAA and TR-O-Glu in monkeys.

4. The binding of tiaramide to plasma protein of the various species of animals and human was about 24–34% and the extent of the binding of tiaramide to human plasma protein was independent of drug concentration within the range of 1–100 μM.     

Species differences in the disposition and metabolism of sulfinpyrazone

1. The disposition and metabolism of sulfinpyrazone have been studied in rats, guineapigs, rabbits, dogs, rhesus monkeys and miniature swine after intravenous administration of 100mg/kg of ¹⁴C-labelled drug.

2. In all species, the integrated plasma concentration (AUC, 0-24h) of total radioactivity was almost completely covered by the sum of the AUC-values of unchanged sulfinpyrazone and six metabolites, i.e. the sulphide, the sulphone, p-hydroxy-sulfinpyrazone, the p-hydroxy-sulphide, the p-hydroxy-sulphone and 4-hydroxy-sulfinpyrazone.

3. Comparison of the plasma level profiles of unchanged sulfinpyrazone and the metabolites revealed pronounced differences between the species. Unchanged sulfinpyrazone was the most prominent compound in plasma of rats, dogs, monkeys and swine, whereas the sulphide metabolite predominated in guinea-pigs. In plasma of rabbits, these two compounds were found in similar amounts.

4. Species with predominant renal excretion of the ¹⁴C dose, i.e. rabbits, dogs and monkeys, eliminated sulfinpyrazone to a high extent unchanged. The renal excretion of the sulphide metabolite was low in all species.

5. Species differences in the biotransformation of sulfinpyrazone explain previously observed differences in inhibitory effect on platelet aggregation. This effect is intensive and long-lasting in species showing high plasma concentrations of the sulphide metabolite.     

Metabolic disposition of 6-ethyl-3-(1H-tetrazol-5-yl)-chromone, a new antiallergic agent, in the rat, guinea-pig, rabbit, dog and monkey.

1. [14C]Ethyltetrazolylchromone ([14C]ETC) was promptly absorbed from the rat small intestine by the portal route. 2. The maximum plasma concn. of unchanged drug after oral administration (10 mg/kg) was highest in dogs (456 microgram/ml), followed by monkeys (287 microgram/ml), guinea-pigs (146 microgram/ml) and rats (55 microgram/ml), and lowest in rabbits (09 microgram/ml). The half-life of the drug in plasma varied with the species, ranging from 13 to 133 h. The drug was highly bound to plasma protein. In dogs and rats, the plasma 14C was predominantly the unchanged drug, whereas in guinea-pigs, rabbits and monkeys it was mainly metabolites. 3. At 10 min after oral administration of the drug to rats there was a wide distribution of the 14C in the tissues. At this time, the 14C concn. were the highest in stomach, followed by kidney, liver, plasma, heart and lung, and lowest in brain. 4. Almost all administered 14C was eliminated from the body in 72 h. The major route of excretion was via the urine except with guinea-pigs, in which animal the 14C was almost equally divided between urine and faeces. 5. only trace amounts of the unchanged drug were found in urine and bile. The major urinary metabolites were as follows: I (1-hydroxyethyl ETC), II (acetyl ETC), III (IIIa, 2-hydroxyethyl ETC) and IV (1,2-dihydroxyethyl ETC) in rats, I and VI (5-carboxymethylsalicylic acid) in guinea-pigs, I, III (IIIb, carboxymethyl ETC) and VII (ETC-N-1-glucuronide) in rabbits, I and VII in dogs, and I and IV in monkeys.     

Comparative pharmacokinetics of nicardipine hydrochloride,a new vasodilator,in various species

1. The pharmacokinetics of a new potent vasodilator, 2-(N-benzyl-N-methylamino)-ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (nicardipine hydrochloride), were studied after oral and i.v. dosage to rats, dogs, monkeys and humans.

2. The plasma half-life and volume of distribution in humans after i.v. administration did not change with dosage in clinical range. In rats and dogs these parameters increased with higher doses, probably because of the potent vasodilative effect of the drug.

3. The plasma clearance in dogs and humans was not affected by dosage, but in rats tended to increase slightly with higher doses.

4. Systemic availability after oral administration was low in spite of excellent absorption, indicating a marked first-pass effect. Increased systemic availability with increased dose indicates that the metabolic activity of the liver may become partly saturated with the drug or its metabolites.

5. Disappearance of the drug from the plasma after i.v. administration was fastest in rats > dogs ≈ monkeys > humans. The terminal half-life of the drug after i.v. administration to humans was about 1?h.     

The availability of carfecillin and its phenol moiety in rat and dog

1. Studies have shown that hydrolysis of carfecillin to carbenicillin and phenol in vitro occurs in blood, liver and gut tissues of rat and dog. Extremely rapid hydrolysis was observed in the blood and liver of the rat.

2. Absorption studies in intestinally-perfused rats showed that following administration of either [¹⁴C]phenol or [phenol-¹⁴C]carfecillin, the half-life values of radioactivity in the intestinal lumen were 6?min and 47?min respectively.

3. Following oral administration of phenol to rats and dogs at 300?mg/kg and 40?mg/kg respectively, maximum plasma concn. of phenol were 26 μg/ml and 7.8 μg/ml. However, following oral administration of carfecillin to rats and dogs at dose levels of 3000 and 800?mg/kg respectively, no significant amounts of free phenol or intact carfecillin were detected (< 1 μg/ml). The very low concentrations of phenol found after carfecillin administration and the concomitant absence of acute phenol toxicity is explained by the slow absorption of carfecillin and its slow hydrolysis to phenol in the gut lumen.

4. In the dog, phenol which enters the portal circulation as carfecillin appears to undergo significant ‘first pass’ metabolism by the liver, while no such effect was observed if free phenol was administered.     

Pharmacokinetics,distribution, and disposition of esaxerenone,a novel,highly potent and selective non-steroidal mineralocorticoid receptor antagonist,in rats and monkeys

1.?Esaxerenone (CS-3150) is a novel non-steroidal mineralocorticoid receptor antagonist. The pharmacokinetics, tissue distribution, excretion, and metabolism of esaxerenone were evaluated in rats and monkeys.

2.?Following intravenous dosing of esaxerenone at 0.1–3?mg/kg, the total body clearance and the volume of distribution were 3.53–6.69?mL/min/kg and 1.47–2.49?L/kg, respectively, in rats, and 2.79–3.69?mL/min/kg and 1.34–1.54?L/kg, respectively, in monkeys. The absolute oral bioavailability was 61.0–127% in rats and 63.7–73.8% in monkeys.

3.?After oral administration of [¹⁴C]esaxerenone, the radioactivity was distributed widely to tissues, with the exception of a low distribution to the central nervous system. Both in rats and in monkeys, following oral administration of [¹⁴C]esaxerenone the main excretion route of the radioactivity was feces.

4.?Five initial metabolic pathways in rats and monkeys were proposed to be N-dealkylation, carboxylation, hydroxymethylation, O-glucuronidation, and O-sulfation. The oxidized metabolism was predominant in rats, while both oxidation and glucuronidation were predominant in monkeys.     

Pharmacokinetics of the selective prostacyclin receptor agonist selexipag in rats,dogs and monkeys

1.?This study examined the pharmacokinetics, distribution, metabolism and excretion of the selective prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-33679). The compounds were investigated following oral and/or intravenous administration to intact rats, dogs and monkeys, and bile-duct-cannulated rats and dogs.

2.?After oral administration of [¹⁴C]selexipag, selexipag was well absorbed in rats and dogs with total recoveries of over 90% of the dose, mainly in the faeces. Biliary excretion was the major elimination pathway for [¹⁴C]MRE-269 as well as [¹⁴C]selexipag, while renal elimination was of little importance. [¹⁴C]Selexipag-related radioactivity was secreted into the milk in lactating rats.

3.?Plasma was analysed for total radioactivity, selexipag and MRE-269 in rats and monkeys. Selexipag was negligible in rat plasma due to extensive metabolism, and MRE-269 was present in rat and monkey plasma. A species difference was clearly evident when selexipag was incubated in rat, dog and monkey plasma.

4.?Total radioactivity was rapidly distributed to tissues. The highest concentrations were found in the bile duct and liver without significant accumulation or persistence, while there was limited melanin-associated binding, penetration of the blood–brain barrier and placental transfer of drug-related materials.     

Species differences in hydrolase activities toward OT-7100 responsible for different bioavailability in rats,dogs, monkeys and humans

OT-7100 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a] pyrimidine) is an amide moiety-bearing pyrazolopyrimidine derivative with a potential analgesic effect. To determine the factors responsible for observed species differences in the bioavailability of this drug, human and experimental animal samples were used to investigate in vitro microsomal and cytosolic hydrolase activities in the liver and small intestine vis-à-vis the pharmacokinetics of OT-7100. The AUC_0–t values of OT-7100 after oral administration in rats, dogs and monkeys were 0.163, 0.0383 and 0.00147?µg?h?ml^?1 divided by mg?kg^?1, respectively. The bioavailabilities of OT-7100 after oral administration in rats, dogs and monkeys were 36, 17 and 0.3%, respectively. The plasma concentration–time profiles of intravenously administrated OT-7100 in rats, dogs and monkeys were similar. The hydrolase activities toward OT-7100 in liver microsomes or cytosol were approximately similar in rats, dogs, monkeys and humans. In contrast, hydrolase activities of small intestinal microsomes from monkeys were higher (36.1?ng?mg?protein^?1?min^?1) than those of rats, dogs and humans (5.4, 1.4 and 4.3?ng?mg?protein^?1?min^?1, respectively). These results suggest that the primary factor influencing first-pass metabolism for the OT-7100 is enzymatic hydrolysis in the small intestine. This information provides an important index for extrapolating the pharmacokinetics of drugs in humans using studies on monkeys.     

Absorption,metabolism and excretion of cobimetinib,an oral MEK inhibitor,in rats and dogs

1.?The absorption, metabolism and excretion of cobimetinib, an allosteric inhibitor of MEK1/2, was characterized in mass balance studies following single oral administration of radiolabeled (¹⁴C) cobimetinib to Sprague–Dawley rats (30?mg/kg) and Beagle dogs (5?mg/kg).

2.?The oral dose of cobimetinib was well absorbed (81% and 71% in rats and dogs, respectively). The maximal plasma concentrations for cobimetinib and total radioactivity were reached at 2–3?h post-dose. Drug-derived radioactivity was fully recovered (～90% of the administered dose) with the majority eliminated in feces via biliary excretion (78% of the dose for rats and 65% for dogs). The recoveries were nearly complete after the first 48?h following dosing.

3.?The metabolic profiles indicated extensive metabolism of cobimetinib prior to its elimination. For rats, the predominant metabolic pathway was hydroxylation at the aromatic core. Lower exposures for cobimetinib and total radioactivity were observed in male rats compared with female rats, which was consistent to in vitro higher clearance of cobimetinib for male rats. For dogs, sequential oxidative reactions occurred at the aliphatic portion of the molecule. Though rat metabolism was well-predicted in vitro with liver microsomes, dog metabolism was not.

4.?Rats and dogs were exposed to the two major human circulating Phase II metabolites, which provided relevant metabolite safety assessment. In general, the extensive sequential oxidative metabolism in dogs, and not the aromatic hydroxylation in rats, was more indicative of the metabolism of cobimetinib in humans.     

Disposition and metabolism of amosulalol hydrochloride,a new combined α- and β-adrenoceptor blocking agent,in rats,dogs and monkeys

1. The disposition and metabolism of amosulalol hydrochloride, a combined α- and β-adrenoceptor blocking agent, were studied in rats, dogs and monkeys.

2. After oral administration of [¹⁴C]amosulalol hydrochloride, the plasma concentration of radioactivity reached a maximum at 05 to 1 h in all species and declined with half-lives of about 2 h in both rats and monkeys, and of about 4 h in dogs. The ratios of unchanged drug to total radioactivity in the rat and dog plasma were 8 and 43% at 05 h after administration, respectively. The radioactivity in the rat tissues was high in the liver, kidney, blood and pancreas after oral administration.

3. Following oral dosage, the urinary excretion of radioactivity was 26-34% of the dose in rats, 45% in dogs and 46% in monkeys in 48 h. The biliary excretion after oral dosage amounted to 66% and 41% in rats and dogs, respectively.

4. Six metabolites were isolated and identified from the urine of rats and dogs. They were derived from one or two of the following pathways: I, hydroxylation of the 2-methyl group of the methylbenzenesulphonamide ring; II, demethylation of the o-methoxy group of the methoxyphenoxy ring; III, hydroxylation at the 4 or 5 position of the methoxy-phenoxy ring; IV, oxidative cleavage of the C—N bond yielding o-methoxyphenoxy acetic acid. Moreover, some metabolites were metabolized to glucuronide or sulphate.     

The metabolism of 4-aminobiphenyl in rat. I. Reaction of N-hydroxy-4-aminobiphenyl with rat blood in vivo

1. ³H-4-Aminobiphenyl (ABP, 5?mg) given i.p. to rat had elimination half-lives of 15.6, 17 and 17?h, respectively, for urinary, faecal and total ³H elimination. ¹⁴C-ABP administered orally to rats at 100?mg/kg gave elimination half-lives of 31, 36.7 and 34?h, respectively, for urinary, faecal and total ¹⁴C elimination.

2. Semi-log plots of percentage dose remaining in the body versus time indicated that: (i) 82% of ³H activity was excreted in 36?h with a half-life of 14.4?h and 18% with a half-life of 46.2?h, and (ii) 77% of ¹⁴C activity was excreted in 48?h with a half-life of 15?h and 23% with a half-life of 180?h.

3. After i.p. injection of 10?mg/kg ¹⁴C-ABP to rats, ferrihaemoglobin (HbFe³⁺) concn increased to 60% in 2h, accompanied by accumulation of ¹⁴C activity in erythrocytes, indicating that the active metabolite, N-hydroxy-4-aminobiphenyl (N-hydroxy-ABP) had oxidized haemoglobin-Fe²⁺ (HbFe²⁺) and was bound to the erythrocyte.

4. ABP given i.p. to rats at 0.24 mmol/kg rapidly appeared in blood, disappeared with a half-life of 30?min, and blood concn plateaued at 30 nmol/ml. The concn of 4-acetyl-aminobiphenyl (AABP) plateaued at 17 nmol/ml after 15?min, indicating a dynamic equilibrium between N-acetylation of ABP and N-deacetylation of AABP. The concn of 4′-hydroxy-4-acetylaminobiphenyl (4′-hydroxy-AABP) increased slowly at 1.65 nmol/h.

5. AABP given i.p. to rats at 0.88 mmol/kg slowly appeared in the blood, accompanied by the appearance of ABP and 4′-hydroxy-AABP and formation of HbFe³⁺. After 4?h the concn of AABP and ABP was 27.35 mmol/ml, indicating a dynamic equilibrium between N-deacetylation of AABP and acetylation of ABP. Neither N-hydroxy-ABP nor N-hydroxy-4-acetylaminobiphenyl (N-hydroxy-AABP) were found.