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.     

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 Cmax 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 (t1/2 beta) of I was 4 h in mice and 9-10 h 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 t1/2 beta of I was decreased to 2.4 h. In rodents the serum clearance and apparent volume of distribution of I were 0.04-0.2 l/kg.h and 0.5-0.8 l/kg, respectively, and 0.6 l/kg.h and 9.8 l/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.     

Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans.

Ifetroban is a potent and selective thromboxane receptor antagonist. This study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of ifetroban after i.v. and oral administrations of [14C]ifetroban or [3H]ifetroban in rats (3 mg/kg), dogs (1 mg/kg), monkeys (1 mg/kg), and humans (50 mg). The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring between 5 and 20 min across species. Plasma terminal elimination half-life was approximately 8 h in rats, approximately 20 h in dogs, approximately 27 h in monkeys, and approximately 22 h in humans. Based on the steady-state volume of distribution, the drug was extensively distributed in tissues. Absolute bioavailability was 25, 35, 23, and 48% in rats, dogs, monkeys, and humans, respectively. Renal excretion was a minor route of elimination in all species, with the majority of the dose being excreted into the feces. After a single oral dose, urinary excretion accounted for 3% of the administered dose in rats and dogs, 14% in monkeys, and 27% in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats with the hydroxylated metabolite at the C-14 position being the major metabolite observed in rat bile. Ifetroban was extensively metabolized after oral administration. Approximately 40 to 50% of the radioactivity in rat and dog plasma was accounted for by parent drug whereas, in humans, approximately 60% of the plasma radioactivity was accounted for by ifetroban acylglucuronide.     

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).     

Biotransformation and pharmacokinetics of grandiflorenic acid [kauradien-9(11),16-oic acid-18]. 3rd communication (author's transl)

Absorption, metabolism and excretion of 14C-GFA following i.v., i.p. and oral application are investigated in rats. After i.p. administration GFA is completely absorbed, after oral dosage about 83% are absorbed. GFA is excreted by 100% via bile and undergoes extensive enterohepatic circulation. After administration of 20 mg/kg 14C-GFA nearly all radioactivity is eliminated after 96 h, more than 80% via the faeces.     

Disposition of sucrose octa-isobutyrate in rats, dogs and monkeys

The disposition of 200 mg/kg of ¹⁴C-labelled sucrose octa-isobutyrate (¹⁴C-SOIB), a component of sucrose acetate isobutyrate (SAIB), a beverage emulsion stabilizer, was studied in rats, dogs and monkeys. After oral administration of ¹⁴C-SOIB to three rats, 3–15% of the dose was excreted as volatile products, 1–2% appeared in urine and 78–93% was recovered in faeces. In dogs, recoveries of radiolabel in CO₂, urine and faeces were approximately 1%, less than 2% and 77–94%, respectively. Monkeys excreted the majority of the dose in faeces; less than 2% of the administered radioactivity was eliminated in either CO₂ or urine. The biliary excretion of radiolabel from ¹⁴C-SOIB was negligible in rats and monkeys; however, in dogs, 3–10% of the dose was excreted into bile. It was demonstrated by chromatographic analyses of faeces that ¹⁴C-SOIB was more extensively hydrolysed in the gastro-intestinal tract of rats and dogs than in monkeys. The results indicate that after oral administration, rats and dogs absorb SOIB following hydrolysis of the sugar ester in the gut. The proportion of the dose that is absorbed by the rat is oxidized to CO₂. In the dog, little of the absorbed product is oxidized; rather, it is circulated through an enterohepatic pathway. In contrast, in the monkey, SOIB is not detectably hydrolysed in the gut or absorbed. These findings show that there is a species difference in the disposition of SOIB; the most salient findings relate to a difference in the disposition of SOIB in the dog compared with the rat.     

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.     

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   

Metabolism of the anti-psoriatic agent 5-methoxypsoralen in humans: comparison with rat and dog.

1. Single oral doses of 14C-5-methoxypsoralen (5-MOP) to human subjects (50 mg), rats (1 mg/kg) and dogs (1 mg/kg) were fairly well absorbed but subjected to extensive first-pass metabolism, at least in rat and human. Means of 62, 51 and 40% dose in urine and 31, 38 and 48% dose in faeces, were excreted by humans (during 5 days), rats (3 days) and dogs (1 day), respectively. In dogs, faecal 14C was probably derived, in part, from biliary excreted material. 2. Total 14C in human plasma reached peak concentrations after 2 h (mean 235 ng 5-MOP equivalent/ml) and declined relatively slowly, to about 60% of this value within 24 h. Unchanged 5-MOP was not detected in plasma using h.p.l.c. (< 5 ng/ml). 3. Tissue concentrations of 14C were generally greater in dogs than rats and reached peak levels at 1 h in dogs but at 24 h in rats. Apart from liver and bile, dog tissue 14C concentrations were lower than those in the corresponding plasma, whereas in rat they were lower only until the time of peak concentrations, after which they were generally greater. 4. 5-MOP was extensively metabolized in all three species. The major 14C-components in human and dog urine were glucuronic acid conjugates, mainly of an arylacetic acid and arylalcohols, resulting from initial oxidative metabolism of the furan ring of 5-MOP. In rat, these metabolites were excreted mainly unconjugated. An unusual metabolite was formed by reduction of the lactone moiety of 5-MOP, probably by the gut flora, giving rise to an arylpropionic acid, excreted as a glucuronic acid conjugate in the urine of all three species. 5. Unchanged drug was a very minor component of human and rat plasma, but a major component of dog plasma. In all three species, circulating 14C-metabolites were similar to those in the urine but were present mainly unconjugated. On the basis of these data, the metabolic fate of 5-MOP in humans was more similar to that in dog than to that in rat, although humans appeared to metabolize 5-MOP more rapidly than did dog.     

Absorption and excretion of suprofen in rats

DL-2-(4-(2-Thienylcarbonyl)phenyl)propionic acid (suprofen, S) was rapidly absorbed in rats after oral administration. Blood levels after a single oral dose of 2, 10, 50, or 100 mg/kg of 3H-S reached maxima within 30 min and were dose-dependent. The major portion of the drug was shown to be absorbed from the upper part of the small intestine and a portion from the stomach. The radioactivity in rat plasma was extensively bound to the plasma protein in vivo; this was found to be unchanged S and four metabolites. Elimination of S and its metabolites from blood was rapid; 3H was mostly excreted in the urine and feces within 24 hr after oral administration of 3H-S. No significant amounts of 14CO2 were excreted in expired air after administration of 14C-S. Rat urine contained S and four metabolites found in rat plasma, accounting for about 60% of the urinary radioactivity. After rats with biliary fistulas were given an oral dose of 2 mg/kg of 3H-S, 41% of the dose was excreted in the bile during 48 hr; there was significant enterohepatic circulation. When single or 21 consecutive daily doses of 3H-S were administered to rats, the blood levels after the multiple doses were higher than those after a single dose but no significant difference was found in excretion of 3H.     

Biotransformation and mass balance of tipranavir, a nonpeptidic protease inhibitor, when co-administered with ritonavir in Sprague-Dawley rats

In this study, tipranavir (TPV) biotransformation and disposition when co-administered with ritonavir (RTV) were characterized in Sprague-Dawley rats. Rats were administered a single intravenous (5 mg kg(-1)) or oral (10 mg kg(-1)) dose of [(14)C]TPV with co-administration of RTV (10 mg kg(-1)). Blood, urine, faeces and bile samples were collected at specified time-points over a period of 168 h. Absorption of TPV-related radioactivity ranged from 53.2-59.6%. Faecal excretion was on average 86.7% and 82.4% (intravenous) and 75.0% and 82.0% (oral) of dosed radioactivity in males and females, respectively. Urinary excretion was on average 4.06% and 6.73% (intravenous) and 9.71% and 8.28% (oral) of dosed radioactivity in males and females, respectively. In bile-duct-cannulated rats, 39.8% of the dose was recovered in bile. After oral administration, unchanged TPV accounted for the majority of the radioactivity in plasma (85.7-96.3%), faeces (71.8-80.1%) and urine (33.3-62.3%). The most abundant metabolite in faeces was an oxidation metabolite R-2 (5.9-7.4% of faecal radioactivity, 4.4-6.1% of dose). In urine, no single metabolite was found to be significant, and comprised <1% of dose. TPV when co-administered with RTV to rats was mainly excreted in feces via bile and the parent compound was the major component in plasma and faeces.     

Absorption,distribution, metabolism and excretion of telmesteine,amucolitic agent,in rat

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of ¹⁴C-telmesteine in the Sprague–Dawley rat.

2. ¹⁴C-telmesteine was rapidly absorbed after oral dosing (20 and 50mg 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 30min 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.     

Systemic lanthanum is excreted in the bile of rats

Lanthanum carbonate is a non-calcium-based oral phosphate binder for the control of hyperphosphataemia in patients with chronic kidney disease Stage 5. As part of its pre-clinical safety evaluation, studies were conducted in rats to determine the extent of absorption and routes of excretion. Following oral gavage of a single 1500 mg/kg dose, the peak plasma lanthanum concentration was 1.04+/-0.31 ng/mL, 8 h post-dose. Lanthanum was almost completely bound to plasma proteins (>99.7%). Within 24h of administration of a single oral dose, 97.8+/-2.84% of the lanthanum was recovered in the faeces of rats. Comparing plasma exposure after oral and intravenous administration of lanthanum yielded an absolute oral bioavailability of 0.0007%. Following intravenous administration of lanthanum chloride (0.3 mg/kg), 74.1+/-5.82% of the dose (96.9+/-0.50% of recovered lanthanum) was excreted in faeces in 42 days, and in bile-duct cannulated rats, 10.0+/-2.46% of the dose (85.6+/-2.97% of recovered lanthanum) was excreted in bile in 5 days. Renal excretion was negligible, with <2% of the intravenous dose recovered in urine. These studies demonstrate that lanthanum undergoes extremely low intestinal absorption and that absorbed drug is predominantly excreted in the bile.     

The pharmacokinetics and metabolism of idazoxan in the rat

1. [2'-14C]Idazoxan was rapidly and completely absorbed after its oral administration to rats. 2. After administration of either [2'-14C] or [6,7-3H]idazoxan, radioactivity was taken up by a wide range of tissues and became localized, especially in the organs of metabolism and excretion. Quantitative distribution patterns were route-dependent such that oral dosing resulted in lower radioactivity concentrations in all tissues apart from liver. 3. Clearance of idazoxan (94-144 ml/min per kg) was due mostly to metabolism and was independent of dose. Oral bioavailability in male rats at low oral doses of idazoxan (10 mg/kg) was about 1%, but increased with increasing dose to 23% at 100 mg/kg. Oral bioavailability in female rats was considerably higher than in male rats, at all doses studied. Brain idazoxan levels were in equilibrium with those in plasma, but ten-fold higher. 4. Elimination of radioactivity after administration of 14C-idazoxan was via the urine and the faeces (about 75% and 20% of dose respectively) and occurred essentially in the 24 h period immediately after dosing. By 96 h after dosing, elimination was virtually complete, with less than 0.5% dose remaining in the carcasses. 5. Biotransformation was by hydroxylation at positions 6 and 7 to form phenolic metabolites, which were excreted as glucuronide and sulphate metabolites in urine, but unconjugated in faeces. Other minor metabolic routes were 5-hydroxylation or oxidative degradation of the imidazoline ring, but these pathways were of quantitatively minor importance in the rat.     

The absorption of [G-3H]-acetylglycyrrhetate after oral administration to rats.

A tritium-labelled form of aluminium acetylglycyrrhetate has been synthesised by catalytic exchange with tritiated water. An oral dose of aluminium [3H]-acetylglycyrrhetate to rats was mainly excreted in the faeces (a mean of 73%). A mean of 4% was excreted in the urine and after five days 17% of the radioactivity was retained in the carcass. The amounts of non-volatile (drug-related radioactivity excreted in faeces and urine during five days were 65% and 3%, respectively, while 6% was retained in the carcass. The total amount of tritiated water produced was 24% of the dose. Experiments in rats with cannulated bile ducts indicated that much of the faecal radioactivity represented unabsorbed drug. 15% of an oral dose was eliminated in bile during 2 days. A minimum value for the extent of absorption of an oral dose was estimated as 21%. Plasma levels of radioactivity were very low and peak levels of drug-related radioactivity were reached at 30 min and represented about 0.2% of the dose in total plasma.     

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.     

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate in rats, dogs and monkeys

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) were studied in rats, dogs and monkeys after administration of [14C]-MN-1695. MN-1695 was found to be well absorbed from the small intestine after oral administration in all species examined. Plasma level of unchanged MN-1695 reached a maximum at 1 to 4 h after oral administration of [14C]-MN-1695 in rats, dogs and monkeys. The mean elimination half-life of unchanged MN-1695 from plasma was about 3, 4 and 50 h in rats, dogs and monkeys, respectively. Tissue levels of radioactivity after oral administration of [14C]-MN-1695 in rats indicated that [14C]-MN-1695 was distributed throughout the body and the radioactivity in tissues disappeared with a rate similar to that in plasma. A stomach autoradiogram after intravenous administration of [14C]-MN-1695 in the rat revealed the radioactivity localized in the gastric mucosa where MN-1695 was assumed to exert its pharmacological activity. In pregnant rats, [14C]-MN-1695 was distributed to the fetus with levels similar to maternal blood levels. After oral administration of [14C]-MN-1695 in rats, 39 to 46% of the dose was excreted into the urine and 50 to 63% of the dose into the feces, within 96 h. In dogs, about 40% of the dose was excreted into the urine and about 50% of the dose into the feces, within 6 days after oral administration. In monkeys, within 14 days after oral administration, about 60 and 30% of the dose were excreted into the urine and feces, respectively, and the main excretion route was the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enterohepatic circulation of radioactivity following an oral dose of [14C]temazepam in the rat

The enterohepatic circulation of radioactive material after administering [14C]temazepam was evaluated in three sets of male Wistar strain rats connected in pairs by bile duct-duodenum cannulae. After a single oral dose (10 mg kg-1) to the donor rat, the excretion of radioactivity in the urine and faeces of both rats and in the bile of the recipient rat was determined. Mean total recovery of the administered radioactivity was 92.2%. Based on the amount remaining in the donor rat (gastrointestinal tract and faeces), 81.7% of the dose was absorbed by the donor. The total amount recovered from the recipient, 69.4% of original dose (85.1% of donor's absorbed dose), represented the amount excreted in the donor's bile. Similarly, 54.1% of the original dose (77.9% of the transferred biliary excretion from donor) was reabsorbed by the recipient, and the biliary excretion from this animal (45.9% original dose) accounted for 86.% of the amount reabsorbed.     

Pharmacokinetics, tissue distribution, and excretion of sitafloxacin, a new fluoroquinolone antibiotic, in rats, dogs, and monkeys

The pharmacokinetics, tissue distribution and excretion of sitafloxacin (CAS 127254-12-0, DU-6859a) were investigated in rats, dogs, and monkeys following single intravenous or single oral administration of 14C-labelled sitafloxacin at a dose of 4.69 mg/kg. Following single administration of the oral dose, serum concentrations of radioactivity peaked at 0.5 h in rats, 2.3 h in dogs, and 2.5 h in monkeys. The apparent absorption ratios of 14C-sitafloxacin based on the AUC0-infinity were 31%, 51%, and 93% in rats, dogs, and monkeys, respectively. In rats, the drug-related radioactivity had been distributed to most organs and tissues 30 min after oral dosing, and had been essentially eliminated after 24 h. The highest levels of radioactivity were observed in the kidneys and liver, whereas the concentrations in the cerebrum and spinal cord were much lower than the serum value. The urinary recoveries of radioactivity after intravenous dosing were 45.5 % in rats, 32.3 % in dogs, and 77.8 % in monkeys. In bile duct-cannulated rats, 57.8 % of the orally administered radioactivity was excreted in the bile within 48 h, and at least 45 % of the sitafloxacin-related material secreted in the bile was re-absorbed from the gastrointestinal tract. These results indicate that sitafloxacin is rapidly absorbed and widely distributed into various tissues. Sitafloxacin-related material is eliminated primarily through both renal and biliary excretion in rats, and possibly in dogs, whereas renal excretion is the major route of elimination in monkeys.