Pharmacokinetics of the thioether phospholipid analogue BM 41.440 in rats.
BM 41.440 (1-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine) is a cytotoxic thioether phospholipid analogue that recently has entered phase I trials in cancer patients. The objective of this study was to evaluate the pharmacokinetics of this compound in female rats after administration of a single oral dose (15 mg/kg body weight [bw] ). Furthermore, BM 41.440 serum concentrations were determined under a daily oral treatment of up to 13 weeks. Blood samples were obtained via permanent catheters from the femoral arteries before and after drug administration for a total of 120 hr. Urine was collected in 24 hr-intervals for 120 hr; the volume was measured, and aliquots were stored at -20 C until analytical determination of the thioether derivative. BM 41.440 was assayed in serum and urine by means of a specific, newly developed reverse-phase high pressure liquid chromatography technique. Mean maximum serum concentrations (1.7 micrograms/ml, n = 4 animals) were attained after seven hr. A terminal half-life of ca. 27 hr was calculated from the rate constant for the terminal elimination phase (lambda z approximately 0.026/hr). The mean serum BM 41.440 concentration-time-area-under-the-curve was 52.9 mg X hr/l. The ratio of total body clearance to absorption fraction was 4.7 ml/min X kg bw. Only a small amount of the drug was found in the urine. The quantity excreted in the urine during a 24 hr-interval never exceeded 1.5% of the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Herrmann
D B
DB
Boehringer Mannheim GmbH, Department of Immunopharmacology and Cancer Research, Federal Republic of Germany.
Besenfelder
E
E
Bicker
U
U
Pahlke
W
W
Böhm
E
E
D000284:Administration, Oral; D000818:Animals; D010755:Organophosphates / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics*; D010742:Phospholipid Ethers / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains
D010755:Organophosphates; D009943:Organophosphorus Compounds; D010742:Phospholipid Ethers; C043297:ilmofosine