Pharmacokinetics of the thioether phospholipid analogue BM 41.440 in rats

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Abstract
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 μg/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 (λz ∼ 0.026/hr). The mean serum BM 41.440 concentration‐time‐area‐under‐the‐curve was 52.9 mg × hr/l. The ratio of total body clearance to absorption fraction was 4.7 ml/min × 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. Under a daily oral schedule (15 mg/kg bw × day) up to 13 weeks, mean BM 41.440 serum concentrations of 3.3±0.5 μg/ml and 5.2±1.2 μg/ml (mean ±S.D., n=10 animals) were found after five and 13 weeks, respectively. Taken together, the data indicate that BM 41.440 was absorbed from the gastrointestinal tract after oral administration and that accumulation of BM 41.440 can occur in rats.