Phase I pharmacokinetic study of the novel antitumor agent SR233377.

SR233377 is a novel thioxanthenone analogue that demonstrated solid tumor selectivity in vitro with activity confirmed in vivo against several murine tumors including those of colon, pancreas, and mammary origin. Its primary preclinical dose-limiting toxicities included myelosuppression and neurological toxicity. The neurological toxicity was acute and could be ameliorated in mice when the drug was administered as a 1-h infusion instead of rapid i.v. injection. As a result of its preclinical efficacy profile, SR233377 entered Phase I clinical investigation. The compound was administered i.v. over 2 h on day 1 repeated every 28 days. The starting dose was 33 mg/m2 (one-tenth the mouse LD10). Escalations continued to 445 mg/m2 (six escalations), where dose-limiting toxicity was observed. At this dose, acute ventricular arrhythmias, including one patient with torsades de pointes and transient cardiac arrest, occurred. Because this toxicity might have been related to the plasma peak, the protocol was amended to a 24-h infusion beginning at 225 mg/m2. With this dose, prolongation of the corrected QT interval (QTc) over the pretreatment levels resulted. Because prolonged QTc is a known forerunner to acute ventricular arrhythmias, clinical development of SR233377 was stopped. However, preclinical antitumor and toxicity studies with analogues are underway with hopes of identifying a new clinical candidate with similar antitumor effects that is devoid of cardiac toxic effects.

beta-carotene intestinal absorption: bile, fatty acid, pH, and flow rate effects on transport.

beta carotene absorption in the unanesthetized rat was investigated by recirculating a micellar perfusate that contained beta-carotene through jejunal and ileal intestinal loops. Radioautography revealed extensive distribution of the provitamin throughout the layers of the small bowel. A linear relationship was found between the concentration of beta-carotene in the perfusate and its rate of absorption at perfusate concentrations of 0.5--11 mM. Increases in the perfusate hydrogen ion concentrations, additions of fatty acids of varied chain lengths and degrees of saturation, and an increase in the perfusate flow rate caused higher rates of beta-carotene absorption. Increase in the perfusate sodium taurocholate concentration above 2.5 microM did not change the absorption rate of beta-carotene. These experiments indicate that beta-carotene absorption takes place by passive diffusion. The process of diffusion can be modulated by intraluminal factors that change the physical characteristics of perfusate or stimulate the intracellular cleavage of carotene to retinal.

Vitamin K2 colonic and ileal in vivo absorption: bile, fatty acids, and pH effects on transport.

Colonic and ileal absorption of vitamin K2 ([2-methyl-3H]menaquinone-9) was investigated in the conscious rat. When the absorption rate was plotted against the perfusate concentration, a linear relationship was found between these two parameters in the ileum and colon. The absorption rate of menaquinone by the ileum was increased as the bile salt concentration, degree of unsaturation of the added long-chain fatty acids, hydrogen ion concentration, and perfusate flow rates were increased. Colonic menaquinone absorption decreased as the bile salt concentration was increased. Menaquinone colonic absoprtion increased as the pH decreased, but no change was noted as the perfusion rate was increased. The present experimental observations in vivo, coupled with prior observations in vitro, indicate that absorption of menaquinone by the ileum and colon occurs by a passive diffusion process that is modified by variations in the perfusate bile salt concentration, the presence of unsaturated fatty acids, and the perfusate pH. The present observations indicate that the mammalian colon and terminal ileum can provide a constant source of vitamin K to aid hemostasis despite episodic lack of dietary vitamin K.