Disodium mercaptoundecahydro-closo-dodecaborate (BSH) is an important compound for boron neutron capture therapy. The pharmacokinetics of boron by BSH were studied in normal rats after rapid intravenous injection at three doses (30, 100, 300 mg/kg) or continuous infusion (100 mg/kg/30 min). The boron concentration in biological samples was measured by inductively coupled plasma atomic emission spectroscopy. The blood half-lives of boron in the elimination phase (t_1/2β) after rapid injection of BSH at doses of 30, 100 and 300 mg/kg were 1.7, 17 and 19 hr, respectively. AUC (32, 219 and 4030 μg·hr/ml) increased with the dose, but there was no proportionality among the values. Total clearance decreased drastically from 233 ml/hr/kg (100 mg/kg) to 38 ml/hr/kg (300 mg/kg). As boron was excreted mainly into urine, these results suggest that renal function failure might occur with dosing of 300 mg/kg. In the case of continuous infusion of 100 mg/kg of BSH for 30 min, the pharmacokinetic parameters were similar to those of rapid injection of 100 mg/kg. The highest boron concentration was observed in the kidney and the lowest in the brain. After multiple dosing of BSH at 100 mg/kg/day×14 days, the boron concentrations in blood, liver, lung and kidney at 24 hr after the last dosing were higher than those after single dosing and were similar to those of simulated values calculated from the single dosing parameters. These results clearly indicated that boron does not accumulate unexpectedly in any tissue with multiple dosing of 100 mg/kg of BSH for two weeks.

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Disodium mercaptoundecahydro-closo-dodecaborate(BSH)の100, 300及び600mg/kgをラットに単回静脈内投与した時の毒性を, 投与速度の影響を含めて検討した。BSHによる中毒症状の主徴は, 投与直後からの全身硬直, 呼吸抑制, 活動性低下及び異常歩行であり, 600mg/kg群では中毒死例が発生した。死亡例は, 投与後10分以内の即時死例と投与5時間後から2日後の遅延死例に大別された。死亡率に明らかな性差並びに投与速度による差はなかったが, 雄の急速群では即時死例が, 雌では投与速度に関係なく遅延死例が多かった。死亡例の病理検査では, 即時死例は肺のうっ血・水腫, 遅延死例は腎近位尿細管壊死が主病変であり, これらが主な死因と推察された。腎障害は, 300mg/kg以上の群で投与翌日には尿細管壊死, 投与7日後は壊死後の再生像で示され, 尿検査, 血液化学的検査でも障害発生が裏付けられ, 投与7日後には貧血も認められた。他の器官障害は致死量である600mg/kg群に限って認められた肝細胞の変性, 心臓の出血・壊死, 下垂体前葉細胞の空胞化, 脳・膵臓の出血等であった。投与5分後の血中ホウ素濃度は, 投与量に比例した値を示し, 明らかな雌雄差もなかった。急速群と低速群の血中ホウ素濃度を同用量間で比較すると, 低速群で低値を示したものの, 顕著な差はなかった。以上のように, BSHのラット単回静脈内投与時の毒性標的は腎臓, 致死量は600mg/kgであった。また, 主な死因は, 即時死例では循環障害, 遅延死例では腎障害であった。

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Disodium mercaptoundecahydro-closo-dodecaborate(BSH)の安全性評価の一環として, 変異原性の有無を検討するため, 遺伝子突然変異誘発性を指標とする細菌を用いる復帰突然変異試験を, S.typhimurium TA100, TA1535, TA98, TA1537およびE.coli WP2uvrAを試験菌として, 156～5000μg/plateの用量でプレインキュベーション法により実施した。その結果, いずれの菌株においても復帰変異コロニー数は陰性対照と同程度かそれ以下で用量依存性の増加傾向は認められず, BSHは本実験条件下の細菌を用いる復帰突然変異試験において陰性と判定され, 変異原性はないものと結論した。

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Triethylenetetramine dihydrochloride (trientine-2HCl, TJA-250), a copper chelating agent used to treat Wilson's disease, was administered orally to male and female F-344 rats for 4 or 8 weeks at dosages of 0, 100, 350 or 1200 mg/kg/day or for 26 weeks at dosages of 50, 175 or 600 mg/kg/day. 4 or 8-week study. Two males receiving 1200 mg/kg/day died during week 8 of treatment. In males receiving 1200 mg/kg/day during weeks 5 to 8 of treatment, body weight gain and food consumption were decreased and hunched posture and thin build were observed. During week 4 or 8 of treatment urinalysis revealed, for males receiving 100 mg/kg/day or animals receiving 350 mg/kg/day or more, increased electrolyte outputs possibly due to the hydrochloride nature of trientine-2HCl, with low plasma alkaline phosphatase activities evident in animals receiving 350 or 1200 mg/kg/day. After 4 and 8 weeks, and during 8 weeks of treatment, high lung weights and bronchiolar epithelium hypertrophy and broncho-alveolar pneumonia were recorded for animals receiving 1200 mg/kg/day, and submucosal acute inflammation within the glandular region of the stomach was recorded for males receiving 350 or 1200 mg/kg/day and in all treated female groups. 26-week study. One male receiving 175 mg/kg/day and three males receiving 600 mg/kg/day died, showing lung changes. The body weight gain of animals receiving 600 mg/kg/day was slightly decreased. Blood chemistry and urinalysis examinations showed changes similar to those indicated in the 4- or 8-week study. The low plasma copper concentrations seen in males receiving 600 mg/kg/day, the slightly low liver copper concentrations found in animals receiving 600 or 175 mg/kg/day and the high urinary copper concentrations found in all treated groups, are attributed to the pharmacological action of trientine-2HCl. Histopathology revealed a dosage-related incidence and severity of focal chronic interstitial pneumonitis accompanied by fibrosis of the alveolar walls in females receiving 175 mg/kg/day or more and all treated male groups, but no significant pathological changes in the stomach. Apart from the histological changes found in the lung, all the above changes were reversible. In conclusion, the NOAEL of trientine-2HCl in this 26-week study was considered to be 50 mg/kg/day for females and less than 50 mg/kg/day for males.

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