The clinical efficacy and safety of BRL25000 (BRL) was objectively compared with that of amoxicillin in patients with chronic respiratory tract infections and those with exacerbated acute infections in a double blind study. Patients over 16 years old with apparent clinical signs and symptoms were administered BRL or AMPC orally q. i. d. for 14 days at a daily dose of 4 tablets (BRL: one tablet contains 250 mg of AMPC and 125 mg of clavulanic acid; AMPC: one tablet contains 250 mg of AMPC). The parameters assessed were clinical efficacy, bacteriological response, rate of improvement of clinical signs and symptoms, appearance of side effects, abnormal laboratory findings and clinical usefulness.
Clinical efficacy was analysed statistically in 275 patients (147 administered BRL, 127 administered AMPC) and 58 patients out of a total of 333 patients were excluded. Side effects were also analysed in 324 patients (BRL: 167, AMPC: 157) in whom judgement was possible.
The following results were obtained.
1. On the basis of committee judgement the overall clinical efficacy rate for the BRL and AMPC treated groups was 83.1% and 71. 7% respectively.
2. Analysis of the 255 cases with chronic respiratory tract infections or acute exacerbations thereof, that is cases that corresponded faithfully to the protocol, showed that the clinical efficacy rate for the BRL and AMPC groups was 82.5% and 69.6% respectively.
Statistical analysis of both sets of these results revealed that BRL was significantly more effective than AMPC (BRL>AMPC, P<0.05). Furthermore analysis based on severity of illness showed that the clinical response to BRL in moderate infections was significantly superior to that of AMPC.
3. The bacteriological elimination rate of causative organisms was 67.4% out of 86 patients treated with BRL and 57.9% out of 77 treated with AMPC. No significant difference was observed between the two drug groups.
4. With respect to the rate of improvement of clinical signs and symptoms the BRL group was superior to the AMPC group in the improvement for dyspnea and sputum appearance seven days after treatment (P<0.05).
5. A number of subjective side effects and abnormal laboratory findings were observed in 37 patients out of 157 in the BRL group and 38 out of 157 in the AMPC group. In all instances these findings were mild and there was no significant inter group difference in incidence.
6. Regarding usefulness as judged by the doctor in charge the respective rates for the BRL group and AMPC group were 74.8% and 62.2% and these assessments were significantly different (BRL>AMPC, P<0.05).
From the above results it was concluded that BRL is a more useful drug than AMPC for the treatment of chronic respiratory tract infections and the significance of the β-lactamase inhibitor clavulanic acid formulated with AMPC was demonstrated clinically.

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A randomised double blind comparison of BRL25000 (1.5 g/day) and amoxicillin (1 g/day), administered orally for 5 consecutive days, was conducted in patients with complicated urinary tract infections. There was no significant difference in the background features or the pretreatment urinary leucocyte and bacterial counts, at least 5 leucocytes/hpf and 104 bacterial cells/ml respectively, of the 234 patients, 186 males and 48 females included in the study. Clinical efficacy, assessed by reduction or elimination of bacteriuria and pyuria, was evaluated according to the criteria established by the UTI committee in Japan.
Analysis of the clinical results showed that BRL25000 was significantly more efficacious (P<0.01) than amoxicillin in the treatment of both monomicrobial 82%(62/76) responded to BRL25000 and 53%(41/78) to amoxicillin therapy, and polymicrobial infections where the observed response to BRL25000 was 63%(24/38) and to amoxicillin 26%(11/42). Excellent plus moderate responses were obtained in 75% of 114 patients receiving BRL25000 and in 43% of 120 patients receiving amoxicillin. Bacteriological evaluation established that BRL 25000 was significantly more effective than amoxicillin in the treatment of infections caused by Escherichia coli, Serratia spp., Klebsiella spp. and Enterobacter spp. and both drugs were highly effective in the treatment of infections caused by gram-positive bacteria. There was no significant difference in the adverse reactions observed between the two treatment groups.
From the results of this study it was concluded that, at the dose levels employed BRL25000 was clinically and bacteriologically more effective than amoxicillin with a comparable low incidence of side effects.

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A double-blind comparison of BRL25000, formulation of amoxicillin and clavulanic acid in 2: 1 ratio, and cefatrizine propylene glycol was carried out in the treatment of complicated urinary tract infections. Patients received either 1, 125 mg of BRL25000 in 3 divided doses or 1, 000 mg of cefatrizine in 4 divided doses a day for 5 days by oral administration.
All patients had pyuria of 5 or more WBCs per high power field, bacteriuria of 104 or more bacteria per ml of urine and underlying urinary disease. The overall clinical efficacy of the treatment was evaluated by the criteria proposed by the UTI Committee in Japan as excellent, moderate or poor.
Of the 297 patients admitted to the study, 147 received BRL25000 and 150 received cefatrizine. No significant difference in background characteristics was observed between the 2 treatment groups. Excellent and moderate responses were obtained in 58. 5% of the patients receiving BRL25000 and 37. 3% of the patients receiving cefatrizine. This difference was statistically significant (P<0.01). The overall bacteriological eradication rates obtained were 78. 9% of 247 strains in the BRL25000 group and 61. 2% of 250 strains in the cefatrizine group. This difference was also significant (P<0. 01). When the bacteriological responses to treatment were compared between the 2 groups according to bacterial species, eradication rates of S. faecalis and Enterobacter were significantly higher in the BRL25000 group.
Subjective side effects were observed in 11 patients (5. 9%) in BRL25000 group and 6 patients (3. 2%) in cefatrizine group. Drug related aggravations of laboratory test results were observed in 7 patients in the BRL25000 group and 5 patients in the cefatrizine group. There were no significant difference between the two treatment groups regarding the incidence of side effects and BRL25000 appeared to be as well tolerated as cefatrizine.
From the results obtained in this study, we concluded that BRL25000 was useful in the treatment of complicated urinary tract infections, especially those in patients without indwelling catheters and was significantly more effective than cefatrizine in those due to S. faecalis, Enterobacter or Serratia.

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BRL25000 is composed of one part of potassium clavulanate and two parts of amoxicillin trihydrate (AMPC). Clavulanic acid inhibits most of the β-lactamases which can inactivate amoxicillin and increase the bactericidal activity of amoxicillin.
BRL25000 and amoxicillin were compared in the management of acute skin infection by double blind test and obtained the following results.
1) Overall clinical evaluation by attending doctors showed that the efficacy rate of BRL25000 was superior to that of amoxicillin (P<0.10). The results of stratified analysis showed that statistically significant better results (P<0.05) were obtained for BRL25000 in the clinical evaluation of severe cases, mature cases, absent concomitant drug cases and cases from which β-lactamase producing S. aureus were isolated.
2) Standardized clinical evaluation showed that there was no statistically significant difference between BRL25000 and amoxicillin, however, the stratified analysis of the results (3rd day evaluation) showed that statistically significant better results (P<O. 05) were obtained for BRL25000 in the clinical evaluation of moderate and immature cases.
3) The bacteriological effectiveness of BRL25000 was superior to amoxicillin (P<0.05).
4) There was no significant difference between BRL25000 and amoxicillin when the results were assured either in terms of improvement at followup on each evaluation day or doctor usefulness.
5) The incidence of side effects was not significantly different between both drugs.
Thus, we conclude BRL25000 has superior clinical efficacy to amoxicillin in the management of acute skin infection.

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We conducted a randomized, double-blind comparison between BRL25000 and amoxicillin in acute purulent otitis media and chronic purulent otitis media acute exacerbation.
259 patients received orally either 1, 125 mg of BRL25000 or 750 mg of amoxicillin three times a day for 7 days.
The clinical responses were obtained in 62.7%(52/83) of patients with acute exacerbation of chronic purulent otitis media treated with BRL25000 and in 46.5%(46/99) of patients treated with amoxicillin, as judged by doctors in charge.
BRL25000 was found to be significantly more effective than amoxicillin in this study.
Bacteriologically, the percentage eradication of causal organisms was 60.0%(57/95) for BRL25000 and 49. 5%(48/97) for amoxicillin.
There was no significant difference in percentage eradication between BRL25000 and AMPC.
The percentage eradication of β-lactamase producing strains of BRL25000 and amoxicillin was 56. 4%(44/78) for BRL25000 and 36.8%(25/68) for amoxicillin: There was a difference of satistical significance.
As to safety of the drugs, the incidence of side effect was 6.4%(8/125) for BRL25000 and 7.0%(9/128) for amoxicillin: There was no significant difference in incidence of side effects.
It was concluded that BRL25000 is significantly more useful than amoxicillin, as judged according to the number of cases with clinical responses “very satisfactory” and “satisfactory”(75 cases for BRL25000 vs. 62 cases for amoxicillin)

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BRL14151K is a newly developed β-lactamase inhibitor and BRL25000 is a formulation consisting of BRL14151K and Amoxicillin in ratio of 1: 2.
We performed an acute toxicity study on BRL14151K and BRL25000, administering these compounds orally, subcutaneously and intraperitoneally to mice and rats, and also a subacute toxicity study administering the compounds orally to rats, for 30 days.
Oral LD₅₀ values were in excess of dose that could be administered in these species for BRL25000, and very high for BRL14151K. The LD₅₀ values were the lowest when the compounds were administered intraperitoneally. Comparisons between species and between sexes, indicated that there was no clear-cut trend toward differences.
In the subacute toxicity study, abdominal swelling, soft feces and diarrhea were seen as general symptoms in the high-dose groups for both test articles. At autopsy, gastric mucosa erosions or mild ulcer were observed at higher doses and an enlarged cecum was seen in all groups which was to be expected in rats treated with antibiotics. On histopathological examination, erosion or mild ulcer [UL-2] of the gastric mucosa was observed at higher doses and deposition of PAS-positive substances in the liver cells were observed. However, since there were no other biochemical or histopathological changes seen in the liver and the change had regressed or was regressing following the off-dose period, this effect is not considered to be of toxicological importance.
Relatively minor changes in hematological and biochemial observations are considered to be secondary to changes observed on the gastro-intestinal tract.

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BRL14151 K (60, 30, and 15 mg/kg) and BRL 25000 (180, 90 and 45 mg/kg) were administeredorally by daily gavage to beagle dogs for 35 days in order to evaluate the subacute toxicity of thesedrugs and the regression of treatment-related effects after a 35-day off-dose period.
Vomiting was noted slightly more frequently in females and males treated with BRL 14151 K at 60 mg/kg, and diarrhea was noted more frequently in females and males treated with BRL 25000 at 180 mg/kg. However, the severity of these symptoms was mild and there were no other behaviouralchanges.
On histopathological examination, a slight swelling of hepatocytes with pale granular appearancewas noted mainly in the high dosed groups of BRL 14151 K and BRL 25000 which regressed completelyduring the off-dose period. There were no other treatment-related effects relating to the liver or anyother hematological, biochemical or histopathological investigations.
In conclusion, very few changes attributable to BRL 14151 K or BRL 25000 were noted in this study. The maximum non-effect dose level was considered to be 30 mg/kg for BRL 14151 K and 90 mg/kg for BRL 25000.
The findings in dogs treated with BRL 25000, a formulation of BRL 14151 K with amoxicillin, were not qualitatively or quantitatively different from those in dogs treated with BRL 14151 K.

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BRL25000 and BRL14151K were administered by daily oral gavage to Sprague-Dawley rats for 26 weeks, the dosage levels in terms of pure free acid being 30, 60, 150 and 1, 200 mg/kg/day BRL25000 and 10, 20, 50 and 400 mg/kg/day BRL14151K. Some rats from the high dose level and control groupson both studies were retained for a further 4 weeks without further dosing before they werekilled. The following were considered to be attributable to the test compounds:
(1) Excessive salivation immediately following dosing at the high dose level with both compounds.
(2) Reduced rate of bodyweight gain in rats receiving 1, 200 mg/kg/day BRL25000 or 400 mg/kg/day BRL14151K, and in males receiving 150 mg/kg/day BRL25000. Food consumption was not affected butwater consumption was increased in rats receiving 1, 200 mg/kg/day BRL25000 and reduced in females receiving 400 mg/kg/day BRL14151K. The effects persisted throughout the withdrawal period in the BRL25000 treated rats, however, rats previously treated with 400 mg/kg/day BRL14151K showedimproved bodyweight gain during the withdrawal period.
(3) Blood and urine examination revealed an increase in the number of circulating lymphocytesin males receiving 1, 200 mg/kg/day BRL25000 and in rats receiving 400 mg/kg/day BRL14151K, and areduction in the activated partial thromboplastin time in males receiving 1, 200 mg/kg/day BRL25000 or 400 mg/kg/day BRL14151K. These changes were not apparent at the end of the withdrawal period.
The concentration of albumin was reduced in males receiving 1, 200 mg/kg/day BRL25000 and, toa lesser extent in those receiving 150 mg/kg/day BRL25000. A similar effect, including decreased totalprotein levels was recorded for rats receiving 400 mg/kg/day BRL14151K and to a lesser extent femalesreceiving 50 mg/kg/day BRL14151K. These differences did not persist during the withdrawal period.
However, at the end of the dosing period the concentration of proteins was reduced in femalesreceiving 1, 200 mg/kg/day BRL25000, mainly due to a reduction in albumin and this differencepersisted throughout the withdrawal period.
A trend towards smaller volumes and high osmolality of the urine voided by rats recieving 400 mg/kg/day BRL14151K was noted, although such a trend was not apparent at the end of thewithdrawal period.
(4) Post mortem examination revealed an increase in liver weight in rats receiving 1, 200 mg/kg/day BRL25000 or 400 mg/kg/day BRL14151K, throughout the withdrawal period in females previously treatedwith 1, 200 mg/kg/day BRL25000 and males previously treated with 400 mg/kg/day BRL14151K.
Microscopic examination showed the following changes in rats that had received 1, 200 mg/kg/day BRL25000 or 400 mg/kg/day BRL14151K.
(a) hepatocyte enlargement in males and females;
(b) hyperplasia of the non-glandular epithelium of the stomach in the region of the limiting ridgein males and females, and
(c) distension of the lumen of the caecum.
The only one of these changes to persist throughout the withdrawal peroid was enlargement ofhepatocytes particularly in male rats on both studies.
(5) It is concluded that maximum no effect level in these studies for BRL25000 and BRL14151K was 150 mg/kg/day and 50 mg/kg/day respectively.

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1. BRL14151K
BRL14151K was administered orally to beagle dogs for six months at dose levels of 5, 10, 20 and 50 mg/kg/day. Particularly at the high-dose level, treatment with BRL14151K caused salivation andemesis. Growth and food and fluid intake were unaffected by treatment with BRL14151K andopthalmological and electrocardiographic studies revealed no effect of compound administration. With the exception of cytoplasmic granulations in the neutrophils, not related to treatment, thefindings of the clinical pathology studies were unremarkable. Histopathology study revealed reversible, hepatic, hydropic vacuolisation in four of eight high-dose dogs after six months of treatment with BRL14151K. There was no evidence of any other hepatic change with BRL14151K. Since thehepatic changes were reversible these are unlikely to have toxicological significance. Ultrastructuralstudy of the liver, kidney and pyloric antrum yielded no evidence of an effect of this drug.
2. BRL25000
BRL25000, an antibiotic formulation of amoxicillin trihydrate and BRL14151K, was administeredorally to beagle dogs for six months at dose levels of 15, 30, 60 and 150 mg/kg/day. There were nodeaths during the study but salivation and emesis were associated with BRL25000 treatment, particularly at the high-dose level. The results of body weight determinations, fluid and foodconsumption measurements, opthalmological studies and electrocardiography were uneventful. Similarly, the results of clinical pathology studies were unremarkable. Cytoplasmic granulations in theneutrophils were observed frequently in high-dose and control dogs. Microscopic examination oftissues revealed reversible hepatic and renal changes in dogs treated with BRL25000 at doses of 30 mg/kg and above. These changes took the form of cytoplasmic glycogen diminution or disappearanceand tubular vacuolisation. The liver change, like that seen BRL14151K, is reversible and noaccompanied by any other hepatic change. The mild kidney change was not dose related alsoreversible and not accompanied by any other evidence of renal toxicity. Therefore the hepatic andrenal changes seen are unlikely to be of toxicological significance. The results of organ weightmeasurements and of ultrastructural studies of the liver, kidneys and pyloric antrum were unremarkable.

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The effects of oral administration of the novel antibiotic BRL25000 and its β-lactamase inhibitorcomponent, BRL14151K, on the course and outcome of pregnancy, have been investigated in rats. These compounds were administered from days 6-15 of gestation inclusive at dose levels of 10, 50 and 400 mg/kg/day for BRL14151K and 30, 150 and 1, 200 mg/kg/day for BRL25000. The number ofviable and non-viable foetuses, early and late resorptions, corpora lutea and malformations wereassessed at caesarean section of dams on day 20 of pregnancy. Other dams were allowed to delivertheir offspring and litter sizes, numbers of live births and stillbirths, gross anomalies and pup growthand survival to weaning were evaluated. In addition, physiological, neuropharmacological and reflexdevelopment and reproductive performance were assessed in the F₁ animals. Both compounds produceda slight degree of maternal toxicity but there were no biologically meaningful effects on any of theparameters examined at caesarean section, on the incidences of malformations, on the physical, behavioural and reproductive capabilities of the F₁ generation, nor were there any adverse effects inthe F₂ generation. In summary, the findings in these studies indicate absence of teratogenic effectsin rats at doses as high as 400 mg/kg/day for BRL14151K and 1, 200 mg/kg/day for BRL25000.

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The novel antibiotic formulation BRL25000 and its β-lactamase inhibitor component BRL14151K weregiven to pregnant rats from Day 15 of gestation until Day 21 of lactation to examine their effects onpeni-and post-natal development. BRL14151K was administerd orally at doses of 10, 50 and 400 mg/kg/day and, in a separate study, BRL25000 was given orally at doses of 30, 150 and 1, 200 mg/kg/day. The dams were allowed to deliver their offspring. Parent animals were assessed for maternaltoxicity, viability, growth, duration of gestation, problems at parturition and maternal instinct. Litter size, number of livebirths and stillbirths, gross anomalies, pup growth and survival to weaningwere evaluated. In addition, physiological, neuropharmacological and reflex development of theoffspring were determined and some were retained to examine their reproductive performance: thefoetal F₂ generation were observed for abnormalities. In BRL14151K study, dose related decreasesoccurred in F₀ maternal body weight gain and food consumption at 50 and 400 mg/kg/day. The durationof gestation and parturition were normal, however. Decrease of pup body weight gain was observedin males and females of 400 mg/kg/day. Treatment with BRL14151K did not adversely affect the numberof stillborn or viable pups per litter at birth nor pup survival indices. Neither did treatment adverselyaffect the physiological or behavioural development or reproductive capabilities of the F1 generation, nor the foetal development of the F2 generation. Treatment with BRL25000 induced no markedmaternal toxicity when given in the pen-natal period. There were no significant observations in thetreated animals, but inhibition of food consumption and body weight gain occurred at 1, 200 mg/kg/day. The duration of gestation and the act of parturition were normal. Some intergroup differences inlitter parameters from birth to weaning were observed but none were considered to be associatedwith treatment. The magnitude of these effects at the highest dose level was only slight. There wereno biologically meaningful differences or dose related trends in any BRL25000 treated group in regardto litter observations, behavioural and developmental indices, neuropharmacological responses orreproductive capabilities in the F₁ generation. The F₂ generation was also unaffected. These resultsindicate absence of potential hazard during the perinatal-postnatal period at doses as high as 50 mg/kg/day for BRL14151K and 1, 200 mg/kg/day for BRL25000.

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Fertility tests on BRL14151K and BRL25000 were carried out in CRJ: SD rats. BRL14151K (10, 50 and 400 mg/kg) and BRL25000 (30, 150 and 1, 200 mg/kg) were given orally to male rats for 63 days and to female rats for 14 days. Males and females treated at the same dose levels were pairedand housed together to observe mating and fertility. In females dosing was continued up to Day 7 of pregnancy to study drug effects on implantation, fetal death and development. For both compounds, temporary salivation, inhibition of weight gain, increase in water intake and increase in liver weightwere noted in high-dose groups. There were no treatment related effects on mating and pregnancyindices or spermatogenesis, oogenesis, insemination ovulation, implantation, and fetal survival, anomalies (viscera and skeleton), growth and sex ratio.

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The pig was used as a non-rodent species to assess the teratogenic potential of BRL 25000. Dosages of 150, 300 and 600 mg/kg/day, were administered by gavage to timedmated domestic pigs (Sus scrofa: Large White) during days 12 to 42 of gestation. Theywere observed daily, food consumption was recorded and sows were weighed regularly.
On day 100±2, the sows were killed, litter values determined and foetuses examinedexternally and internally for visceral defects. The foetuses were X-rayed in 2 planes fordetection of skeletal changes.
Structural changes were classified as malformations when rare and/or detrimental tosurvival, as anomalies when not considered detrimental to survival and as variants whendeviations occurred with relatively high frequency. Classification of skeletal variants included assessment of the distribution of presac Tal vertebrae, number of sternebral centres, variations in caudal vertebrae.
Although the highest dosage of 600 mg/kg/day elicited a maternal toxic response namelyinappetence and reduced bodyweight gain, there was no evidence of any selective embryopathic (teratogenic or embryolethal) effect as assessed by values for litter size, embryofoetal mortality, foetal weight and incidences of malformations, anomalies and variantsthis species.

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General pharmacological properties of BRL25000 and its components, BRL14151K and AMPC, were studied by oral administration. In behavioral observation, slight diarrhea and slimy feaces were noted in mice and rats treated with BRL25000 at 1, 800 mg/kg, BRL14151K at doses of 150 mg/kg and above or AMPC at 1, 200 mg/kg.
In observation of rabbit spontaneous EEG, the arousal pattern trended to increase when treated with BRL25000 at 1, 800 mg/kg and BRL14151K at 600 mg/kg. There were no other effects on the central nervous system.
In cats, a reduction in blood pressure, an increase in respiration rate and a slight increase in heart rate were noted, but there were no changes in ECG, when treated with BRL14151K at 600 mg/kg. No changes in movement of isolated guinea pig heart rate were noted. There were no effects on peripheral nervous system. As to effects on smooth muscle and autonomic nervous system, except slight increase in spontaneous motility of isolated rabbit ileum with BRL25000 or BRL14151K at concentrations of 10^-4g/ml, no effects were confirmed.
In digestive system, gastric motility in situ was inhibited in rabbits and secretion of gastric juice in rats, when treated with BRL25000 at doses of 450 mg/kg and above or BRL14151K at doses of 150 mg/kg and above. Intestinal motility increased in mice treated with BRL25000 at 1, 800 mg/kg or BRL14151K at 600 mg/kg.
In renal function tests, inhibition of urine volume and urinary excretion of Na⁺ and Cl^- and reduction in PSP excretion were observed in rats treated with BRL25000 at doses of 450 mg/kg and above or BRL14151K at doses of 150 mg/kg and above. No other effects, such as those on bile excretion, blood coagulation, hemolysis, ICG excretion, blood glucose value, FFA value, TG value, sensory organs and enzyme induction were observed.

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BRL14151K and ¹⁴C-BRL14151K were given to rats to study their absorption, distribution, excretion and metabolism.
The following results were obtained.
1. About 80% of administered ¹⁴C-BRL14151K was rapidly absorbed from the G. I. tract.
2. ¹⁴C-BRL14151K was partly metabolised or degraded in the G. I. tract, but it was rapidly metabolised after absorption. It was found that 26% of the administered dose was metabolised and excreted into expired air as ¹⁴CO₂, and 24% was excreted in urine as unchanged BRL14151. Biliary excretion of radioactivity was only 1.8% of the administered dose.
3. Tissue concentrations of radioactivity were high in kidney, liver, pancreas, Harderian gland, and salivary gland and low in fat and the central nervous system.
4. There were only slight differences in metabolic fate between fasting rats and non-fasting rats.
5. When ¹⁴C-BRL14151K was administered repeatedly, accumulation of radioactive material wasnoted in most tissues examined and particulally in fat. However, the observed accumulation and retention did not affect the excretion.

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BRL14151K and ¹⁴C-BRL14151K were administered to rats and dogs in order to study dose-response relationships, sex differences, distribution to fetuses and milk, species differences and the effect due to repeat dosing.
The following results were obtained.
1. The dose of ¹⁴C-BRL14151K was increased from 15 mg/kg up to 150 mg/kg, and metabolic fate at the different doses was studied. Between the 15 mg/kg dosed group and the 50 mg/kg dosed group, there was no difference in metabolic fate of BRL14151. However there was a slight difference in metabolic fate between the 15 and 150 mg/kg dosed groups.
2. When ¹⁴C-BRL14151K was administered to pregnant and lactating rats, it was found that the radioactivity distributed to the fetuses and was excreted in the milk.
3. There were in general no clear sex differences in the metabolic fate of BRL14151 in rats and dogs.
4. Absorption and excretion of ¹⁴C-BRL14151K in dogs were similar to those in rats. However, there was a difference in metabolism between these two species. BRL14151 was metabolized more slowly in dogs than in rats.
5. Repeated administration of BRL14151K did not affect the metabolic fate of BRL14151 in dogs.

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BRL25000, ¹⁴C-BRL25000 and amoxicillin (AMPC) were administered to rats and dogs in order to study the change in metabolic fate of BRL14151 and AMPC after administration of BRL25000.
The following results were obtained.
1. The metabolic fates of BRL14151 and AMPC were not changed when they were administered to rats as the formulation BRL25000 or as ¹⁴C-BRL25000.
2. For both BRL14151 and AMPC, the extent of protein binding to rat and human plasma was low and there was no evidence of any interaction between the two components when formulated as BRL25000.
3. When BRL25000 was repeatedly administered to dogs, the metabolic fate of BRL14151 and AMPC was not influenced. At any time measured, there was no change in the plasma AMPC/BRL14151 ratio with the increased number of doses administered.

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