Summary
The pharmacokinetics and toxicity of (-)-(S)-bromofosfamide ((2S)-(2-chloroethyl-amino)-3-(2-bromoethyl)-1,3,2-oxaza-phosphorinae 2-oxide, CAS 146452-37-1, CBM-11) were determined in ten patients with non-small cell lung cancer following an oral dose of 1.38 g/m2 B.S.A. (Body Surface Area). The drug was given as a powder in gelatine capsules to fasting patients. Plasma samples were collected during the first 24 h after administration. All samples, after extraction with chloroform, were assayed by a reverse phase HPLC method using UV detection at 200 nm. Orally administered (-)-(S)-bromofosfamide showed relatively fast absorption kinetics. Peak concentration of 47 ?g/ml was observed after 1 h. The average half-life was about 5 h. Toxicities associated with oral (-)-(S)-bromofosf-amide therapy consisted of symptoms regarding the central nervous system, gastrointestinal tract and urinary tract. Neurotoxic symptoms were the most common clinically significant side effects and probably dose limiting.
S)-Bromofosfamide ((2S)-(2-chloroethylamino)-3-(2-bromoethyl)-1,3,2-oxa-zaphosphorinane 2-oxide, CAS 146452-37-1, CBM-11) is a new potential anticancer drug, currently under investigation. Its pharmacokinetics and bioavailability were studied in female mice following intravenous and oral administration of the dose of 50 mg/kg. The compound was extracted from plasma samples using chloroform and analyzed by high-performance liquid chromatography with UV detection at 200 nm. Orally administered (−)-(S)-bromofosfamide was absorbed quickly, attaining a maximum level of 33.9 µg/ml at 5 min, and was eliminated with a half-
Zusammenfassung Pharmakokinetik von (−)-(S)-Bromofosfamid nach intravenöser und oraler Applikation bei Mäusen(−)-(S)-Bromofosfamid ((2S)-(2-Chlorethylamino)-3-(2-bromoethyl)-1,3,2-oxazaphosphorinane-2-oxid, CAS 146452-37-1, CBM-11) ist ein neues potentielles Krebsheilmittel, das zur Zeit untersucht wird. Pharmakokinetik und Bioverfügbar-keit nach intravenöser und oraler Applikation in einer Dosierung von 50 mg/kg wurden bei Mäusen untersucht. Die Verbindung wurde aus Plasmaproben mit Chloroform extrahiert und mit Hilfe von HPLC (UV-Detection bei 200 nm) analysiert. (−)-(S)-Bromofosfamid wurde nach oraler Applikation rasch resorbiert, wobei der Maximalspiegel (33,9 µg/ml) nach life (t 1/2 ) of about 0.9 h. The average half-life of intravenously administered (−)-(S)-bromofosfamide was about 0.7 h. The total plasma clearance (CL) and volume of distribution (V d ) were found to be 0.14 l/h and 4.92 l/kg, respectively. The absolute bioavailability of (−)-(S)-bromofosfamide after oral administration was 105 %. 5 min erreicht wurde, und mit einer Halbwertszeit (t 1/2 ) von ca. 0,9 h eliminiert. Intravenös appliziertes (−)-(S)-Bromofosfamid wies eine Halbwertszeit von ca. 0,7 h auf. Die Gesamtclearance aus Plasma (CL) und Verteilungsvolumen (V d ) betrug 0,14 l/h bzw. 4,92 l/kg. Die absolute Bioverfügbarkeit von (−)-(S)-Bromofosfamid nach oraler Applikation betrug 105 %. Arzneim.-Forsch./Drug Res. 51 (II), 596−599 (2001) 596 Kobyliń ska et al. − Bromofosfamide
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