Biotransformation of sufentanil in liver microsomes of rats, dogs, and humans

The biotransformation of sufentanil (SUF), an analog of the synthetic opioids fentanyl and alfentanil, was investigated in liver microsomes of rats, dogs, and humans. The drug was extensively metabolized and the metabolism was found to be very similar, both kinetically and metabolically, in the three species. The initial metabolism of SUF occurred monophasically in man and dog and biphasically in the rat over a concentration range of 0.13-20.1 microM. The apparent Vm values were 7.30 and 6.15 nmol metabolized.min-1.mg protein-1, and the apparent Km values were 4.98 microM and 15.2 microM for dog and human microsomes, respectively. In rat microsomes, apparent Km values were 0.10 and 20.8 microM, and the apparent Vm values were 0.10 and 7.32 nmol metabolized.min-1.mg protein-1 for the high and low affinity site, respectively. The major metabolic pathways were similar in the three species and included oxidative N-dealkylation at the piperidine nitrogen, oxidative N-dealkylation of the piperidine ring from the phenylpropanamide nitrogen, oxidative O-demethylation, and aromatic hydroxylation. Desmethyl-SUF was formed at the shorter incubation times but quickly metabolized into secondary metabolites. The major metabolites which could be detected at the end of the incubation were N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, N-[4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide, and N-phenylpropanamide. The relevance of the in vitro results is discussed in relation to previous in vivo studies of the metabolism of SUF in rats, dogs, and humans.     

Metabolism of alfentanil by isolated hepatocytes of rat and dog

1. The biotransformation of ³H-alfentanil was studied using suspension cultures of isolated hepatocytes of male and female rats and of dogs.

2. In hepatocytes of the male rat, alfentanil was readily metabolized, following linear Michaelis-Menten kinetics over the concentration range 5—400μM. The metabolism was strongly inhibited by the cytochrome P-450 inhibitors metyrapone, α-naphthoflavone and piperonyl butoxide.

3. The major metabolites of alfentanil, which were formed in suspension cultures of male rat hepatocytes, were identified by h.p.l.c. co-chromatography and by mass spec-trometry and included N-[4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide. N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide or noralfentanil and N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1-H-tetrazol-1-yl)ethyl]-4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide or desmethylalfentanil.

4. The major in-vitro metabolic pathways of alfentanil in hepatocytes of the three sources were oxidative N-dealkylation at the piperidine nitrogen and oxidative O-demethylation at the methoxymethyl moiety.     

Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat

The metabolism and disposition of tri-p-cresyl phosphate (TPCP) were studied in the rat after a single oral administration of [methyl-14C] TPCP. At a dosage of 7.8 mg/kg, most of the administered radioactivity was excreted in the urine (41%) and feces (44%) in 7 days. For 3 days, the expiratory excretion as 14CO2 amounted to 18% of the radioactivity, but was reduced to 3% by treatment of the animal with neomycin. In separate rats, the biliary excretion amounted to 28% of the dose in 24 hr. At a dose of 89.6 mg/kg, the radioactivity was excreted in urine (12%) and feces (77%) in 7 days, and the expired air (6%) in 3 days. At 24, 72, and 168 hr after oral administration, the concentration of radioactivity was relatively high in adipose tissue, liver, and kidney. The major urinary metabolites were p-hydroxybenzoic acid, di-p-cresyl phosphate (DCP), and p-cresyl p-carboxyphenyl phosphate (1coDCP). The biliary metabolites were DCP, 1coDCP, and the oxidized triesters, di-p-cresyl p-carboxyphenyl phosphate (1coTPCP), and p-cresyl di-p-carboxyphenyl phosphate (2coTPCP). The main fecal metabolite was TPCP, and the others were similar to those of bile. Following oral administration, TPCP was absorbed from the intestine, distributed to the fatty tissues, and moderately metabolized to a variety of products of oxidation and dearylation of TPCP, which were then excreted in the urine, feces, bile, and expired air. The intestinal microflora appeared to play an important role in degrading biliary metabolites to 14CO2 through the enterohepatic circulation in rats.     

The metabolic disposition of etodolac in rats, dogs, and man

The metabolic disposition of etodolac (etodolic acid) was studied after oral and intravenous administration of the 14C-labeled or unlabeled drug to rats and dogs, and after oral administration of the drug to man. In all species, peak serum drug levels were attained within 2 hr after dosing. In rats and dogs, virtually all of the oral dose was absorbed; etodolac represented 95% of the serum radioactivity in rats and 75% in dogs. Serum levels in all species were generally dose-related. The elimination portion of the serum drug concentration/time curves was characterized by several peaks, which in rats were shown to be due to enterohepatic circulation. Tissue distribution studies in rats showed that radioactivity localized primarily in blood vessels, connective tissue, and highly vascularized organs (liver, heart, lung, and kidney) and that the rate of elimination of radioactivity from tissues was similar to that found in the serum. The apparent elimination half-life of etodolac averaged 17 hr in rats, 10 hr in dogs, and 7 hr in man. Etodolac was extensively bound to serum proteins. Liver microsomal cytochrome P-450 levels were unaltered in rats given etodolac daily for 1 week. The primary route of excretion in rats and dogs was via the bile into the feces. Preliminary biotransformation studies in dogs showed the presence of the glucuronide conjugate of etodolac in bile, but not in the urine. Glucuronide conjugates were not seen in the rat. Four hydroxylated metabolites in rat bile were tentatively identified. It was concluded that, in rats and dogs, etodolac is well absorbed, is subject to extensive enterohepatic circulation, undergoes partial biotransformation, and is excreted primarily into the feces.U     

The metabolic disposition of aprepitant, a substance P receptor antagonist, in rats and dogs.

The absorption, metabolism, and excretion of [14C]aprepitant, a potent and selective human substance P receptor antagonist for the treatment of chemotherapy-induced nausea and vomiting, was evaluated in rats and dogs. Aprepitant was metabolized extensively and no parent drug was detected in the urine of either species. The elimination of drug-related radioactivity, after i.v. or p.o. administration of [14C]aprepitant, was mainly via biliary excretion in rats and by way of both biliary and urinary excretion in dogs. Aprepitant was the major component in the plasma at the early time points (up to 8 h), and plasma metabolite profiles of aprepitant were qualitatively similar in rats and dogs. Several oxidative metabolites of aprepitant, derived from N-dealkylation, oxidation, and opening of the morpholine ring, were detected in the plasma. Glucuronidation represented an important pathway in the metabolism and excretion of aprepitant in rats and dogs. An acid-labile glucuronide of [14C]aprepitant accounted for approximately 18% of the oral dose in rat bile. The instability of this glucuronide, coupled with its presence in bile but absence in feces, suggested the potential for enterohepatic circulation of aprepitant via this conjugate. In dogs, the glucuronide of [14C]aprepitant, together with four glucuronides derived from phase I metabolites, were present as major metabolites in the bile, accounting collectively for approximately 14% of the radioactive dose over a 4- to 24-h period after i.v. dosing. Two very polar carboxylic acids, namely, 4-fluoro-alpha-hydroxybenzeneacetic acid and 4-fluoro-alpha-oxobenzeneacetic acid, were the predominant drug-related entities in rat and dog urine.     

Absorption, metabolism and excretion of ketanserin in man after oral administration

The absorption, metabolism and excretion of ketanserin [+)-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)- quinazolinedione, R 41 468), a novel serotonin S2-receptor antagonist used in hypertension, was studied after a single oral dose of 14C-ketanserin tartrate in three healthy subjects. Absorption from the gastrointestinal tract was rapid and almost complete. The excretion of radioactivity amounted to about 90% after 4 days and was more abundant in urine (68%) than in faeces (24%). Ketone reduction and oxidative N-dealkylation at the piperidine nitrogen were by far the two main metabolic pathways. The former pathway resulted in ketanserin-ol, the main metabolite in plasma as well as in urine (24% of dose) and faeces (5%), the latter pathway in the urinary metabolite 1,4-dihydro-2,4-dioxo-3(2H)quinazolineacetic acid (20%). Other pathways were aromatic hydroxylation at the quinazolinedione moiety and the formation of ether glucuronides. None of the metabolites substantially contributes to the overall pharmacological activity of ketanserin. The metabolic pathways of ketanserin in man were identical to those revealed previously in rats and dogs, but the mass balance of the major metabolites resembled more that in dogs than that in rats.     

Evaluation of the absorption, excretion, and metabolism of the antihypertensive agent RWJ-26899 in male and female CR Wistar rats and Beagle dogs.

The absorption, excretion and metabolism of N-(2, 6-dichlorophenyl)-beta-[[(1-methylcyclohexyl)methoxylmethyl]-N-(phenylmethyl)-1-pyrrolidineethanamine (RWJ-26899; McN-6497) has been investigated in male and female CR Wistar rats and beagle dogs. Radiolabeled [14C] RWJ-26899 was administered to rats as a single 24 mg/kg suspension dose while the dogs received 15 mg/kg capsules. Plasma (0-36 h; rat and 0-48 h; dog), urine (0-192 h; rat and dog) and fecal (0-192 h; rat and dog) samples were collected and analyzed. There were no significant gender differences observed in the data. The terminal half-life of the total radioactivity for rats from plasma was estimated to be 7.7 +/- 0.6 h while for dogs it was 22.9 +/- 4.4 h. Recoveries of total radioactivity in urine and feces for rats were 8.7 +/- 2.9% and 88.3 +/- 10.4% of the dose, respectively. Recoveries of total radioactivity in urine and feces for dogs were 4.1 +/- 1.4% and 90.0 +/- 4.7% of the dose, respectively. RWJ-26899 and a total of nine metabolites were isolated and tentatively identified in rat urine, and fecal extracts. Unchanged RWJ-26899 accounted for approximately 1% of the dose in rat urine and 8% in rat feces. RWJ-26899 and a total of four metabolites were isolated and identified in dog urine, and fecal extracts. Unchanged RWJ-26899 accounted for approximately 1% of the dose in urine and 63% in feces in dog. Five proposed pathways were used to describe the metabolites found in rats: N-oxidation, oxidative N-debenzylation, pyrrolidinyl ring hydroxylation, phenyl hydroxylation and methyl or cyclohexyl hydroxylation. Two biotransformation pathways in dogs are proposed: N-oxidation and methyl or cyclohexyl ring hydroxylation.     

Pharmacokinetics and metabolism of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat, dog, and man

The pharmacokinetics and metabolism of advantame were evaluated in rats, dogs, and humans. The oral pharmacokinetic studies using (14)C-advantame showed that advantame undergoes rapid but incomplete absorption, with an oral bioavailability of total radioactivity in the range of 4-23%. Data indicated that absorption was mainly as ANS9801-acid (de-esterified advantame), which was formed in the gastrointestinal tract as a result of the hydrolysis of the methyl ester group of the parent compound. In the dog, plasma ANS9801-acid was present largely in the form of an unidentified conjugate. Advantame (chiefly in the form of metabolites) was mainly excreted in the feces in rats, dogs, and humans (>80% in each species), with urinary excretion representing a minor route. The predominant metabolite of (14)C-advantame detected in the feces and the urine of rats, dogs, and humans was ANS9801-acid, with lower amounts of 3-[3-hydroxy-4-methoxyphenyl]-1-propylamine (termed HU-1) or N-(3-(3-hydroxy-4-methoxy phenyl))propyl-L-aspartic acid (termed HF-1) present, as well as other minor metabolites and areas of indistinct radioactivity. ANS9801-acid, HU-1, and HF-1 were detected and identified in the urine of rats, humans, and dogs, while ANS9801-acid and HF-1 were identified in the feces of humans and dogs. In the feces of rats, in addition to ANS9801-acid, other additional metabolites were detected, including demethylated ANS9801-acid (designated as RF-1) and another unidentified metabolite (designated as RF-2). Overall, the data show generally similar pharmacokinetics of advantame and ANS9801-acid in animals and in humans and close similarity with neotame. Metabolites of advantame that occur in humans are also found in the 2 species utilized in the toxicology studies, and the metabolism studies support the interpretation of safety data from studies conducted in rats and dogs.     

Excretion and biotransformation of cisapride in rats after oral administration

The excretion and biotransformation of cisapride, a novel gastrokinetic drug, were studied after single (10, 40, and 160 mg/kg) and repeated (10 mg/kg/day) po administration to rats, using three different radiolabels. In fasted rats, cisapride was absorbed almost completely, except for the 160 mg/kg dose. Cisapride was metabolized extensively to at least 30 metabolites. The excretion of the metabolites amounted to more than 80% of the dose at 24 hr and was almost complete at 96 hr after dosing. In bile duct-cannulated rats, 60% was excreted in the bile within 24 hr, 45% of which underwent enterohepatic circulation. The main urinary metabolites, 4-fluorophenyl sulfate and norcisapride, primarily resulted from the N-dealkylation at the piperidine. Another major metabolic pathway was aromatic hydroxylation, occurring on either the 4-fluorophenoxy or the benzamide rings. The resulting phenolic metabolites were eliminated as conjugates in the bile; a large portion of them were subjected to a rapid enterohepatic circulation before their final excretion in the feces. Minor metabolic pathways included piperidine oxidation, O-dealkylation, O-demethylation of the methoxy substituent at the benzamide, and amine glucuronidation. Only minor quantitative dose- and sex-dependent differences could be observed for the mass balance of the metabolites. Upon repeated po dosing, steady state excretion rates were already attained after two to three doses, and excretion and metabolite patterns were very similar to those after single dose administration.     

Metabolic fate of the new cardiotonic denopamine in animals. 1st communication: absorption, distribution and excretion in the rat, rabbit and dog

Absorption, distribution and excretion of (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino] ethanol (denopamine, TA-064) a new positive inotropic agent, were studied after oral and intravenous administration of 3H- or 14C-denopamine (5 mg/kg) to different animal species. After oral administration to rats, rabbits and dogs, the time to attain the peak and the maximum concentration of the plasma levels of radioactivity were about 15 min, 4 micrograms eq./ml in rats, 15-45 min, 8 micrograms eq./ml in rabbits and 2-4 h, 2 micrograms eq./ml in dogs, respectively. The plasma denopamine levels in dogs reached the peak (0.34 microgram/ml) at 0.5-3 h after administration, and thereafter gradually decreased with half-lives of 1.6-3.1 h. Following oral administration to rats, the amounts remaining of the parent compound in the digestive tract at 0.5 and 3 h after administration were about 27 and 2% of the dose administered, respectively. This indicated that the compound was rapidly and almost completely absorbed from the intestinal tract. When 3H-denopamine was orally administered to rats, cumulative excretion of radioactivity in the urine and feces within 24 h were about 60 and 32% of the dose, respectively. Almost 100% of the dose were recovered from the urine and feces within 120 h. About 50% of the dose administered were excreted in the bile within 24 h. The occurrence of enterohepatic circulation was indicated in rats. Distribution of radioactivity was investigated in rats by means of whole body autoradiography and the tracer technique.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glutathione conjugate formation from hexachlorocyclohexane and pentachlorocyclohexene by rat liver in vitro

1. Metabolites of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were extracted from the bile of TCDD-treated dogs and administered by gavage to bile-duct-cannulated rats and also to an intact rat.

2. Radioactivity of the TCDD metabolites was rapidly cleared from the body of the rats, indicating that bioaccumulation of these compounds does not occur.

3. Biliary excretion was the most important route of elimination in the cannulated rats and amounted to > 30% of the administered dose within 24h. TCDD metabolites were also eliminated to a minor extent by the kidneys. The combined recovery of radioactivity in faeces, bile and urine after 24h accounted for >85% of the dose.

4. The intact animal exhibited a somewhat different kinetic behaviour in that only 13% dose was excreted in faeces and urine after 24h, which indicates enterohepatic circulation. The administered radioactivity was completely recovered after 72?h.

5. Results from the present experiments indicate that metabolism of TCDD is the ratelimiting step in elimination of TCDD from the liver. Interspecies variability in the toxicity of TCDD may in part be attributable to different rates at which the species metabolize and excrete TCDD.     

Evaluation of the excretion, and metabolism of the cardiotonic agent bemoradan in male rats and female beagle dogs.

The excretion and metabolism of (+/-) [6-(3,4-dihydro-3-oxo-1,4[2H]-benzoxazine-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one] (bemoradan; RWJ-22867) have been investigated in male Long-Evans rats and female beagle dogs. Radiolabeled [14C] bemoradan was administered to rats as a singkle 1 mg/kg suspension dose while the dogs received 0.1 mg/kg suspension dose. Plasma (0-24 h; rat and dog), urine (0-72 h; rat and dog) and fecal (0-72 h; rat and dog) samples were collected and analyzed. The terminal half-life of the total radioactivity for rats from plasma was estimate to be 4.3 +/- 0.1 h while for dogs it was 7.5 +/- 1.3 h. Recoveries of total radioactivity in urine and feces for rats were 49.1 +/- 2.4% and 51.1 +/- 4.9% of th dose, respectively. Recoveries of total radioactivity in urine and feces for dogs were 56.2 +/- 12.0% and 42.7 V 9.9% of the dose, respectively. Bemoradan and a total of nine metabolites were isolated and tentatively identified in rat and dog plasma, urine, and fecal extracts. Unchanged bemoradan accounted for approimately < 2% of the dose in rat urine and 20% in rat feces. Unchanged bemoradan accounted for approximately 5% of the dose in urine and 16% in feces in dog. Six proposed pathways were used to describe the metabolites found in rats and dogs: pyridazinyl oxidations, methyl hydroxylation, hydration, N-oxidation, dehydration and phase II conjugations.     

Hepatobiliary elimination of bendamustin (Cytostasan) in rats.

Biliary excretion of bendamustin (Cytostasan, 5-[bis(2-chloroethyl)amino]-i-methylbenzimidazole-2-butyric acid; 1) and its metabolites was studied in rats after i.v. administration of 14C-1. The most significant finding was the rapid excretion of 1 related radioactivity in the bile occurring shortly after injection. While radioactivity eliminated by bile within 2 h was 41.8%, in the course of subsequent 22 h it amounted only to 3.2%. Bile samples analyzed by TLC indicated that the total amount of radioactivity was excreted in the form of conjugates and two hydroxy metabolites. A significant amount of radioactivity was excreted in urine. The diversion of bile by cannulation of the bile duct led to a significant decrease of elimination by feces.     

Biotransformation and excretion of N,N'-bis(3-(2-ethoxyphenoxy)-2-hydroxypropyl)ethylenediamine dihydrochloride (Falirytmin) in rats

Falirytmin (1) was metabolized in rats almost completely. Besides small amounts of 1 in urine and feces 18 metabolites could be separated. The proposed structures of 14 compounds demonstrate aromatic hydroxylation, N- and O-dealkylation, side-chain oxidation, alcohol dehydrogenation and N-acetylation. The main route of excretion of 1 and metabolites was with the feces. After p.o. or i.v. administration of 14C-O-ethyl-1 the average excretion of radioactivity in urine, feces and expired air was about 75% in 96 h. The residual activity in organs was about 2-2.5%. Whole-body autoradiography confirms these results. Only slight 14C-activity was seen in muscle, fat, liver, bone marrow and gut.     

Excretion and biotransformation of cisapride in dogs and humans after oral administration

The excretion and biotransformation of cisapride, a novel gastrokinetic drug, were studied after a single po dose of [14C]cisapride in dogs and humans. The excretion of radioactivity amounted to 97% within 4 days after a 1 mg/kg dose in dogs (72% in feces and 25% in urine). After a 10-mg dose in humans, 44% was excreted in the 0-24-hr urine and 37% in the 0-35-hr feces; excretion was complete within 4 days. Excretion of the parent drug was greater in dogs (0.4-1.3% of the dose in urine, 23% in feces) than in humans (0.2% in urine, 4-6% in feces). This was due, at least in part, to a larger proportion of amine glucuronidation and sulfation in dogs. N-Deal-kylation at the piperidine nitrogen resulting in the main urinary metabolite, norcisapride, and aromatic hydroxylation of the 4-fluorophenyl ring were major metabolic pathways in both species. Norcisapride excretion accounted for 14% of the dose in dogs and 41-45% in humans. Minor metabolic pathways were O-dealkylation at the 4-fluorophenoxy group and piperidine oxidation. Peak plasma levels and AUC values of norcisapride in humans were 8-9 times lower than those of cisapride. Apart from more amine conjugation in dogs, the biotransformation of cisapride was similar in dogs and humans.     

Pharmacokinetics, enterohepatic circulation and biotransformation of [2-3H]-9,9-Dimethylacridane-10-carboxylic acid S-(2-dimethylamino) thiolethyl ester in the rat and dog

Dogs receiving a 7.5 mg/kg oral or i.v. dose of tritium labelled 9,9-dimethylacridane-10-carboxylic acid S-(2-dimethylamino)thiolethyl ester (DMA) as the methane sulfonate salt (DMA-MS) excreted 86-95% of the radioactivity within 6 days. A similar recovery was obtained for rats receiving 300 mg/kg orally of 15 mg/kg i.v. In both species, approximately 66% of the dose was excreted in the feces as metabolites. Absorption of the oral dose was shown to be 80% and 100% for the rat and dog, respectively. Up to 47% of an i.v. dose was excreted in the bile of rats and an efficient enterohepatic circulation process insues. The parent drug is rapidly metabolized in the tissues yielding at least 6 polar metabolites which contribute to relatively long plasma half-lives in the order of 40 h for dogs and 58-90 h for rats. An atypical increase in plasma radioactivity following an i.v. dose could be rationalized in view of these results. Metabolite profiles were examined in plasma, urine, bile and feces and found to be qualitatively similar. Des-methyl-DMA and DMA-N-oxide were identified as two minor metabolites.     

The pharmacokinetics of nitrendipine. I. Absorption, plasma concentrations, and excretion after single administration of [14C]nitrendipine to rats and dogs

[14C]nitrendipine (3-ethyl 5-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, Bay e 5009, Baypress, Bayotensin) was administered to rats and dogs (intravenously, orally, intraduodenally, 0.5-50 mg/kg) in order to investigate absorption, disposition, and excretion of parent compound and metabolites. The absorption of radioactivity following oral administration of [14C]nitrendipine was rapid and almost complete in both species. Maximum concentrations of total radioactivity in plasma were reached after 1.2 (rat) or 0.7 h (dog). The radioactivity was eliminated from plasma with terminal half-lives of 57 (rat) and 188 h (dog) during an observation period up to 10 and 9 days, respectively. Unchanged nitrendipine contributed to the AUC of total radioactivity only 8-9% after intravenous and 1-2% after oral administration. The bioavailability of nitrendipine after oral administration amounted to 12% in rats and 29% in dogs due to a strong first pass elimination process. About two thirds of the radioactivity administered were excreted via faeces, one third via urine. Distinct sex-differences in the excretion pattern could be found in rats but not in mice. They were attributed to well-known sex differences of the metabolic capacities in rat liver. In rats the radioactivity excreted via bile (about 75% of the dose) was subject to a marked entero-hepatic circulation, about 50% of the amount excreted being reabsorbed. The radioactive residues in the body were low (0.5% of the dose after 2 days in rats; less than or equal to 0.6% after 9 days in dogs).     

Absorption, distribution, metabolism and excretion of 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)- 1,4-dihydropyridine (PP-1466) in rats

In this experiment, the absorption, excretion, distribution and metabolism of 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)-1, 4-dihydropyridine (PP-1466) were investigated following oral or intravenous administration, single dose or repeated dose administration using male SLC-Wistar rats and the results of this investigation were summarized as follows: After oral administration of 14C-PP-1466 to rats, the blood level reached the maximum at 1 h and decreased with the biological half-life of about 5 h. The unchanged drug concentration in plasma was 30% of total concentration in plasma and disappeared at 6 h. The high radioactivities in the liver, kidney, fat, lung and adrenal gland were observed after oral and intravenous administration. After oral and intravenous administrations, the excretion in feces and urine during 48 h was 63.0 and 32.4, 58.6 and 41.6%, respectively. Biliary excretion amounted to 57.6 and 46.2% during 48 h, respectively. Six metabolites were found in the urine of rats. Three of them were identified as 2,6-dimethyl-3-carbomethoxy-4-(2-difluoromethoxyphenyl)-5-carboxylic acid pyridine, 2-methyl-3-carbomethoxy-4-(2-difluoromethoxyphenyl)-5-carboxylic acid-6-hydroxymethyl pyridine and its lactonizing analogue. These three metabolites covered 54% of total urinary metabolites. After oral repeated administration for three weeks, the excretion ratio of radioactivity in urine and feces was constant during the administration and no accumulation was observed in rat tissues.     

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.     

Absorption, distribution, metabolism, and excretion of donepezil (Aricept) after a single oral administration to Rat.

Donepezil hydrochloride (Aricept) is a drug for the treatment of Alzheimer's disease. The absorption, distribution, metabolism, and excretion of donepezil were investigated in male Sprague-Dawley rats after a single oral administration. Orally administered (14)C-labeled donepezil was absorbed rapidly. The plasma level of unchanged donepezil declined more rapidly than that of radioactivity, and the brain level of radioactivity declined almost in parallel with the plasma level of unchanged donepezil. The ratio of donepezil to total radioactivity in brain was 86.9 to 93.0%, indicating low permeability of the metabolites through the blood-brain barrier. No heterogeneous localization of radioactivity was recognized in the brain and the concentration in each part of the brain was 1.74 to 2.24 times the plasma concentration. Cumulative biliary, urinary, and fecal excretion of radioactivity in bile duct-cannulated rats was 72.9, 24.4, and 8.84%, respectively, of the administered radioactivity at 48 h after administration. These results indicate that the absorption of donepezil is almost complete, and that its metabolites are mainly excreted into feces through the bile and some of them are subject to enterohepatic circulation. The metabolism of donepezil was extensive in rats and involved O-demethylation, aromatic hydroxylation, N-dealkylation, N-oxidation, and glucuronide conjugation of O-demethylate. The structures of the metabolites were determined by mass spectrometry and (1)H-NMR analysis. In plasma, urine, and bile, O-glucuronides accounted for the majority of the radioactivity, and in brain, unchanged donepezil was mostly detected. No metabolites were found in brain. There was no notable accumulation of radioactivity in whole blood and tissues.