Pharmacokinetics of nimodipine. I. Communication: absorption, concentration in plasma and excretion after single administration of [14C]nimodipine in rat, dog and monkey

Studies on absorption, plasma concentrations and excretion with (+/-)isopropyl-2-methoxyethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate (nimodipine, Bay e 9736, Nimotop) have been conducted in rat, dog and monkey using the carbon-14-labelled substance and a wide range of doses (0.05-10 mg/kg) administered via different routes (intravenous, oral, intraduodenal). Nimodipine was well absorbed in all species. Peak plasma concentrations of radioactivity were determined 28-40 min (male rat), 60 min (female rat), about 3 h (dog) and 7 h (monkey) after administration. Dependent on the observation period (24-216 h) terminal half-lives for the elimination of radioactivity from plasma ranging between 4.6 h (female rat) and 157 h (dog) were observed. Comparing the AUC, the concentration of unchanged [14C]nimodipine in plasma represented only a small (maximally 37% in dogs after i.v. dose) to negligible (about 1%, monkey after oral dosing) part of the total radioactivity. Excretion of radioactivity via feces and urine was rapid in all species after both oral and intravenous dosing. Fecal (biliary) excretion was the major excretory route in rat and dog. The monkeys excreted about 40 to 50% via the urine. Residues in the body never exceeded 1.5% of the dose. [14C]nimodipine and/or its radiolabelled metabolites were secreted in milk of orally dosed lactating rats. Binding of [14C]nimodipine to plasma proteins of rat and dog was about 97%.     

Absorption, distribution and excretion of lacidipine, a dihydropyridine calcium antagonist, in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog). 2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism. 3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug. 4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species. 5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses. 6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration. 7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Absorption,distribution and excretion of lacidipine,a dihydropyridine calcium antagonist,in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog).

2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism.

3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug.

4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species.

5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses.

6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration.

7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Pharmacokinetics of nisoldipine. I. Absorption, concentration in plasma, and excretion after single administration of [14C]nisoldipine in rats, dogs, monkey, and swine

The absorption, disposition and excretion of (+/-) 3-isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) have been studied following a single administration of the 14C-labelled compound to rats, dogs, monkey and swine via different routes (intravenous, oral, intraduodenal) in the dose range of 0.05-10 mg.kg-1. [14C]nisoldipine was absorbed rapidly and almost completely. Peak concentrations of radioactivity in plasma were reached 0.9 h (rat), 1.4 h (dog), and 3.6 h (monkey) after oral administration with normalized maximum concentrations being in the same range for all three species (0.49-0.79). The radioactivity was eliminated from plasma with half-lives between 42 h and 54 h within an observation period up to 3 days. The contribution of unchanged [14C]nisoldipine to the concentration of total radioactivity in plasma was low after oral administration (between 0.5% (monkey) and 3.4% (dog) in the peak) indicating an extensive presystemic elimination of this compound. The bioavailability was estimated at 3.4% in rats and 11.7% in dogs. [14C]nisoldipine was highly bound to plasma proteins with free fractions of 0.9-2.9%. The excretion of the radioactivity via urine and feces/bile both after oral and intravenous administration of [14C]nisoldipine occurred rapidly and almost completely within 48 h in all species. Very small residues in the body were recovered at the end of the experiments in rats and dogs (less than 1.6% of the dose). The biliary/fecal route of excretion was preferred in rats, dogs and swine, whereas in monkey 76% of the dose was excreted renally.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Absorption,distribution and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats and dogs

1. The absorption, distribution and excretion of nilvadipine have been studied in male rats and dogs after an i.v. (1 mg/kg for rats, 0.1 mg/kg for dogs) and oral dose (10 mg/kg for rats, 1 mg/kg for dogs) of ¹⁴C-nilvadipine.

2. Nilvadipine was rapidly and almost completely absorbed after oral dosing in both species; oral bioavailability was 4.3% in rats and 37.0% in dogs due to extensive first-pass metabolism. The ratios of unchanged drug to radioactivity in plasma after oral dosing were 0.4–3.5% in rats and 10.4–22.6% in dogs. The half-lives of radioactivity in plasma after i.v. and oral dosing were similar, i.e. 8–10h in rats, estimated from 2 to 24 h after dosing and 1.5 d in dogs, estimated from 1 to 3 d. In contrast, plasma concentrations of unchanged drug after i.v. dosing declined biexponentially with terminal phase half-lives of 1.2 h in rats and 4.4 h in dogs.

3. After i.v. dosing to rats, radioactivity was rapidly distributed to various tissues, and maintained in high concentrations in the liver and kidneys. In contrast, after oral dosing to rats, radioactivity was distributed mainly in liver and kidneys.

4. With both routes of dosing, urinary excretion of radioactivity was 21–24% dose in rats and 56–61% in dogs, mainly in 24 h. After i.v. dosing to bile duct-cannulated rats, 75% of the radioactive dose was excreted in the bile. Only traces of unchanged drug were excreted in urine and bile.     

Absorption,distribution, metabolism and excretion of telmesteine,a mucolitic agent,in rat

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of (14)C-telmesteine in the Sprague-Dawley rat. 2. (14)C-telmesteine was rapidly absorbed after oral dosing (20 and 50 mg kg(-1)) with an oral bioavailability of >90% both in male and female rats. The C(max) and area under the curve of the radioactivity in plasma increased proportionally to the administered dose and those values in female rats were 30% higher than in male rats. 3. Telmesteine was distributed over all organs except for brain and the tissue/plasma ratio of the radioactivity 30 min after dosing was relatively low with a range of 0.1-0.8 except for excretory organs. 4. Excretion of the radioactivity was 86% of the dose in the urine and 0.6% in the faeces up to 7 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 3% for the first 24 h. The unchanged compound mainly accounted for the radioactivity in the urine and plasma. 5. Telmesteine was hardly metabolized in microsomal incubations. A glucuronide conjugate was detected in the urine and bile, but the amount of glucuronide was less than 6% of excreted radioactivity.     

Pharmacokinetics of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist. 1st communication: absorption and excretion in rats after a single administration of 14C-NS-49.

The absorption and excretion of NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride, CAS 137431-04-0), a phenethylamine class alpha 1A-adrenoceptor agonist, were studied in rats after a single administration of 14C-NS-49. In addition, the protein binding of this drug was investigated in vivo and in vitro. After oral administration of 14C-NS-49 (1 mg/kg) to male rats, the radioactivity concentrations in the blood and plasma reached maximums within 1 h, then decreased biexponentially with respective elimination half-lives of 25.4 and 11.9 h. Most of the plasma radioactivity was due to unchanged NS-49, indicating of the poor metabolism of this drug in rats. The results of the in situ absorption study using the intestinal loop method showed that 14C-NS-49 was well absorbed from the small intestine. Systemic availability was high (86%), as determined by a comparison of the areas under the plasma concentration-time curves of unchanged NS-49 for oral and intravenous administrations. Food affected the absorption of NS-49. There were no significant sex-related differences in the plasma concentration profiles after the intravenous administration of 14C-NS-49 (p > 0.05). NS-49 was primarily eliminated by renal excretion, 76% and 62% of the dose being excreted unchanged in the urine after intravenous and oral administrations, respectively. The absorption rate, determined on the basis of the urinary excretion of radioactivity, was 83%, being almost the same as the systemic availability. First-pass metabolism of NS-49, therefore, is considered to be very limited in rats. The excretion of radioactivity in the bile within 48 h after the oral administration of 14C-NS-49 (1 mg/kg) was 5.9% of the dose, and the excretion of radioactivity in the exhaled air after the intravenous administration (0.2 mg/kg) was negligible. The percentage of 14C-NS-49 bound to serum proteins in vitro was less than 15% in all the animal species tested. The percentage of radioactivity bound to rat serum proteins after the oral administration of 14C-NS-49 (1 mg/kg) was 16-21%.     

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 and excretion of the new thienopyridine agent prasugrel in rats

Prasugrel is converted to the pharmacologically active metabolite after oral dosing in vivo. In this study, (14)C-prasugrel or prasugrel was administered to rats at a dose of 5 mg kg(-1). After oral and intravenous dosing, the values of AUC(0-infinity) of total radioactivity were 36.2 and 47.1 microg eqx h ml(-1), respectively. Oral dosing of unlabeled prasugrel showed the second highest AUC(0-8) of the active metabolite of six metabolites analyzed. Quantitative whole body autoradiography showed high radioactivity concentrations in tissues for absorption and excretion at 1 h after oral administration, and were low at 72 h. The excretion of radioactivity in the urine and feces were 20.2% and 78.7%, respectively, after oral dosing. Most radioactivity after oral dosing was excreted in bile (90.1%), which was reabsorbed moderately (62.4%). The results showed that orally administered prasugrel was rapidly and fully absorbed and efficiently converted to the active metabolite with no marked distribution in a particular tissue.     

Metabolic fate of the new Ca++-channel blocking agent (+)-(2S,3S)-3-acetoxy-8-chloro-(2-(dimethylamino)ethyl)-2,3-dihydro- 2-(4-methoxyphenyl)-2,5-benzothiazepin-4-(5H)-one maleate. Distribution, excretion and protein binding in rats and dogs

Distribution, excretion and protein binding of (+)-(2S,3S)-3-acetoxy-8-chloro-(2-(dimethylamino)ethyl)-2,3-dihydro- 2-(4-methoxyphenyl)-2,5-benzothiazepin-4-(5H)-one maleate (TA-3090) in rats and dogs were investigated after oral (30 mg/kg (rats), 2 mg/kg(dogs] and intravenous (3 mg/kg (rats), 0.2 mg/kg (dogs) administration of 14C-TA-3090. Plasma level of radioactivity in rats reached plateau (6.04 micrograms equiv. of TA-3090 free base/ml) 1 h after oral administration. The plateau level continued at least up to 6 h. The plasma concentration of the unchanged drug (free base) reached the maximum (425 ng/ml) at 45 min after oral administration, and then decreased with a half-life of 1.16 h. Plasma level of radioactivity after intravenous administration to rats rose gradually up to 1 h and thereafter it was kept constant for 6 h. Plasma concentration of the unchanged drug decreased with half-lives of 0.43 h (alpha phase) and 1.33 h (beta phase) after intravenous administration. In dogs, the peak level of plasma radioactivity after oral administration was 227 ng/ml at 1 h. The Cmax, Tmax and t1/2 of unchanged drug were 31 ng/ml, 1.34 h and 4.13 h, respectively. The plasma levels of total radioactivity and unchanged drug after intravenous administration to dogs were 146 and 142 ng/ml at 1 min, respectively. The t1/2 of the plasma radioactivity were 0.02 h (alpha) and 4.02 h (beta). Those of unchanged drug were 0.03 h (alpha) and 1.66 h (beta).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of ciprofloxacin. 2nd communication: distribution to and elimination from tissues and organs following single or repeated administration of [14C]ciprofloxacin in albino rats

1-Cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-[U-14C]piperazinyl)-3-quinoline carboxylic acid (ciprofloxacin, Bay o 9867; designated tradename: Ciprobay) was administered to male and to pregnant albino rats with single intravenous or oral doses of 5 or 10 mg/kg body weight and with repeated oral doses of 5 mg/kg (7 consecutive daily administrations to male rats). Following a single intravenous administration the [14C]ciprofloxacin related radioactivity was distributed rapidly and differentiated to the body. Compared to plasma high concentrations were determined in kidney, liver, skeleton muscle, pancreas, testes and cartilage, low concentrations occurred in brain and adipose tissue. In some selected tissues radioactivity was largely due to unchanged [14C]ciprofloxacin (57% to 100%). A good penetration of total radioactivity into tissues and organs with a similar distribution pattern as detected after intravenous dosing also occurred after a single oral administration. Highest concentrations were determined 1 h after dosing. Compared to plasma most tissues and organs showed higher concentrations and higher AUC-values. For brain and eye low values were determined. Compared to plasma a longer mean residence time of radioactivity was calculated for brain, eye, eye-wall, testes and blood cells. 6 d after single administration the radioactive residues in the body exclusive gastrointestinal tract amounted to less than 0.1% of the dose. Following a seven-day treatment the distribution pattern of total radioactivity in the body did not differ essentially from that after single dosing. Compared to single dosing AUC-values higher by the factor 2 to 4 were calculated after repeated administration for plasma and most of the tissues and organs.(ABSTRACT TRUNCATED AT 250 WORDS)     

The absorption, distribution, metabolism and elimination of bevirimat in rats

Bevirimat is the first drug in the class of maturation inhibitors, which treat HIV infection by disrupting the activity of HIV protease enzyme with a mechanism of action distinct from that of conventional protease inhibitors. The absorption, distribution, metabolism and elimination characteristics of single intravenous (25 mg/kg) and oral (25 mg/kg and 600 mg/kg) doses of 14C-bevirimat were studied in male Sprague Dawley and Long Evans rats. Pharmacokinetic and mass-balance studies revealed that bevirimat was cleared rapidly (within 12-24 h) after dosing, although plasma radioactivity was quantifiable up to 168 h. Radioactive metabolites of bevirimat were responsible for approximately 60-80% of plasma radioactivity. Systemically available bevirimat was predominantly (97%) excreted via bile in the faeces, with 相似文献   

Pharmacokinetics of 4-acetylaminophenylacetic acid. 1st communication: absorption, distribution, metabolism and excretion in mice, rats, dogs and monkeys after single administration of 14C-labeled compound

Absorption, distribution, metabolism and excretion of 4-acetylaminophenylacetic acid (MS-932) were studied in mice, rats, dogs and monkeys after intravenous or oral administration of 5 or 10 mg/kg of 14C-MS-932. After the intravenous injection of 14C-MS-932, the radioactivity concentrations in the plasma decreased biexponentially. The half-lives of the elimination phase (t1/2, beta) were 2.58 h for mice, 2.35 h for rats, 1.88 h for dogs and 1.24 h for monkeys. After the oral administration of 14C-MS-932, the radioactivity concentrations in the plasma reached maximums between 0.4 and 1.3 h, thereafter decreasing with half-lives similar to those found for the intravenous injection. The systemic availability of this drug was 72-100% in all the species tested. No clear sex-related difference in radioactivity concentrations was found in rat plasma. After both intravenous and oral administrations, in all the species tested, almost all the radioactivity administered was excreted in the urine. Biliary excretion of radioactivity in bile duct-cannulated rats was only 1.42% of the intravenous dose over a 24-h period. Lymphatic absorption of radioactivity was negligible (0.2% of the dose over a 6-h period). After oral administration of 14C-MS-932, the radioactivity concentrations in the rat tissues tested reached maximums within 1 h, decreasing rapidly thereafter similar to the decrease in the concentration in the plasma. Much higher concentrations were present in the kidney and gastro-intestinal tract than in the plasma, whereas the concentrations in the other tissues were lower. Results obtained by whole-body autoradiography were consistent with those obtained for the radioactivity in excised tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist. 2nd communication: Absorption and excretion in rabbits, dogs and monkeys after a single administration of 14C-NS-49.

The absorption and excretion of NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride, CAS 137431-04-0), a phenethylamine class alpha 1A-adrenoceptor agonist, were studied in male rabbits, dogs, and monkeys after intravenous or oral administration of 14C-NS-49. After single oral administration of 14C-NS-49 (1 mg/kg) to rabbits and dogs, the plasma concentrations of radioactivity and NS-49 reached maximums at about 2 h, then decreased triexponentially. In monkeys, both maximums were reached 3 h after administration, and both concentrations decreased biexponentially. Most of the plasma radioactivity was due to unchanged NS-49 in the rabbits and dogs, indicating poor metabolism of this drug. In the monkeys, however, the percentage of unchanged NS-49 in the plasma radioactivity was low, about 20%, during a 24-h period after oral administration. After intravenous and oral administrations of 14C-NS-49, radioactivity was primarily excreted in the urine in all the species tested. The absorption rates found by comparing the urinary excretions of radioactivity after both routes of administration were 71% for rabbits, 92% for dogs, and 95% for monkeys. The percentages of NS-49 in the radioactivity excreted in the urine after intravenous and oral administrations, respectively, were 77% and 68% for rabbits, 96% and 96% for dogs, and 57% and 29% for monkeys. The systemic availability calculated from the unchanged drug excreted in the urine was similar to the absorption rates for rabbits and dogs. This indicates that first-pass metabolism of this drug is very limited in both species. The systemic availability for monkeys, however, was about half the absorption rate due to the first-pass effect. Renal clearance accounted for most of the total clearance for rabbits and dogs, but only about half that for monkeys.     

Pharmacokinetics and metabolism of the antiarrhythmic agent [3H]-diprafenone in the rat

After acute intravenous (i.v.) administration of 3 mg/kg of 3H-labelled 2'[2-hydroxy-3-(1,1-dimethylpropylamino)propoxy]-3-phenylproiop henon hydrochloride ([3H]-diprafenone), plasma radioactivity levels declined biphasically with half-lives of 0.2 h (alpha-phase) and 1.5 h (beta-phase), respectively. After acute oral administration of 9 mg/kg, absorption was prompt but continued, similar to a zero-order process, over many hours resulting in plateau-like plasma levels up to 5-6 h and a subsequent slow decline with a beta-half-life of 6-8 h. Absorption varied between 50 and 80%. Distribution of [3H]-diprafenone was rapid and tissue levels in general paralleled blood levels. After i.v. dosing highest levels of radioactivity were found in the lung; after oral application in the gastrointestinal tract. Radioactivity was distributed into subcellular organelles and the cytosol resulting in an apparent volume of distribution (Varea) of 4-5 l/kg. About 95% of the 3H-activity given was excreted in urine (20%) and faeces (75%) within 48 h after i.v. administration. After oral application, total 3H-recovery was substantially lower. After i.v. dosing most of the 3H-label found in faeces originated from biliary excretion and was almost completed within 4 h after administration. After oral application, biliary excretion varied between about 5 and 35% indicating protracted absorption. 3H-radioactivity was reabsorbed and subject to extensive enterohepatic cycling. After repetitive oral administration, total radioactivity reached a steady state after 4-5 days. The corresponding cumulation factors R ranged between 2 and 3. A decline in elimination rate is likely. [3H]-Diprafenone was metabolized rapidly and quantitatively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition and urinary metabolic pattern of cabergoline,a potent dopaminergic agonist,in rat,monkey and man

1. The disposition and urinary metabolic pattern of ¹⁴C-cabergoline was studied in rat, monkey and man after oral administration of the labelled drug.

2. In all species radioactivity was mainly excreted in faeces, with urinary excretion accounting for 11, 13 and 22% of the dose in rat, monkey and man, respectively.

3. After oral treatment, biliary excretion of radioactivity in rat accounted for 19% of the dose within 24?h.

4. Unchanged drug in 0-24-h urine samples of rat, monkey and man amounted to 20, 9 and 10% of urinary radioactivity, respectively. In the 24-72-h urine samples of all species the relative percentage of unchanged drug increased compared with that measured in the 0-24-h urine.

5. The main metabolite was the acid derivative (FCE21589), which in 0-24-h urine samples of rat, monkey and man accounted for 30, 21 and 41% of urinary radioactivity, respectively.

6. Other metabolites identified in urine of all species resulted from hydrolysis of the urea moiety, the loss of the 3-dimethylaminopropyl group and the deallylation of the piperidine nitrogen.     

Identification of an N-oxide as the major metabolite of the analgesic O-(diethylaminoethyl)-4-chlorobenzaldoxime hydrochloride in dogs

1. After oral administration to dogs of the analgesic O-(diethylaminoethyl)-4-chloro[7-14C]benzaldoxime hydrochloride together with piperazine hydrochloride (2:1, w/w), at a dose of 4.5 mg/kg, the radioactivity was well absorbed and rapidly excreted. During 5 days, 81 percent of the dose (ca. 50 percent in 12 h) was excreted in urine and 10 percent 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 microgram equiv./ml) occurred at 90 min after an oral dose and were higher than those at 2 min following an equivalent intravenous (3.4 microgram equiv./ml) or rectal (4.0 microgram 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 percent and 23 percent dose excreted in the urine of males and females respectively during 12 h after 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)     

Pharmacokinetics and tissue distribution of ketanserin in rat, rabbit and dog

The plasma kinetics and tissue distribution of ketanserin [+)-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)- quinazolinedione, R 41 468) were studied in the rat, rabbit and dog. The studies were performed utilizing 3H- and 14C-labelled ketanserin and appropriate techniques to measure levels of radioactivity, unchanged drug and a major metabolite ketanserin-ol in plasma and tissues. Following intravenous administration to male rats and dogs (10 mg/kg), plasma levels could be described by a two-compartment model. The plasma clearance (C1) averaged 3.8 and 19.2 ml/min/kg and the volume of distribution (Vdss) 0.67 and 4.7 l/kg in male rats and in dogs, respectively. Following oral administration (10-40 mg/kg), ketanserin was rapidly and completely absorbed in all species studied. The absolute bioavailability of oral ketanserin was more than 80% in both rats and dogs. Due to the high clearance of the metabolites in rats, ketanserin was the main component of the plasma radioactivity. In dogs, the fraction of the metabolite ketanserin-ol was more pronounced than that of ketanserin. The apparent elimination half-life of ketanserin was 1.5 h in rabbits, 2-5 h in rats and 3-15 in dogs. The pharmacokinetics of ketanserin were dose-related after single and chronic intravenous and oral dosing. Distribution studies in rats after intravenous and oral administration (10 mg/kg) demonstrated an almost immediate equilibrium between plasma and tissues, resulting in slightly higher tissue than plasma concentrations in the well perfused tissues, and similar or slightly lower levels in the remaining tissues. Ketanserin was the main component of tissue radioactivity. The drug crossed the blood-brain barrier only to a slight extent, brain levels of the unchanged drug being similar to the free fraction in plasma. Ketanserin disappeared from tissues with a similar half-life to that in plasma. On repeated dosing, a small fraction of metabolites was more slowly eliminated. The excretion of the urinary and faecal metabolites after repeated dosing was very similar to that after a single dose. Placental transfer of ketanserin in the rat was limited. On average 0.3% of the maternal radioactive dose, preferentially metabolites, was recovered from the combined foetuses. In dogs orally treated with doses of up to 40 mg/kg/d for 12 months, no undue accumulation or retention of ketanserin or ketanserin-ol was found in any tissue. In lactating dogs orally dosed at 10 mg/kg, preferentially metabolites were excreted in the milk. Concentrations of ketanserin and ketanserin-ol in the milk were respectively 2 and 4 times higher than plasma levels.