THE BIOAVAILABILITY AND DOSE-DEPENDENCY OF THE DEUTERATED ANTITUMOR AGENT 4,6-BENZYLIDENE-D(1)-D-GLUCOSE IN MICE AND RATS

The benzaldehyde derivative 4,6-benzylidene-D-glucose (BG) induces an inhibition of protein synthesis at otherwise non-toxic doses in cells grown in vitro. To increase the biological effect of BG, the hydrogen in the formyl group was exchanged with deuterium, resulting in 4,6-ben zylidene-d(1)-D-glucose (P-1013). In this study we compared the bioava ilability of BG and P-1013, since both intraperitoneal and, especially , oral administration of the drugs would be a great advantage. We also examined whether or not P-1013 displays dose-dependent pharmacokineti cs. Pharmacokinetics were studied by analysing plasma samples using re versed-phase high-performance liquid chromatography (HPLC). P-1013 was given at four different doses i.v, (60, 120, 145 and 230 mg/kg) and p .o. (60, 120, 170 and 230 mg/kg) to female Bom:NMRI-nu mice. The bioav ailability was more than 50% for all doses. The results also indicate that P-1013 shows linear pharmacokinetics, with no change being observ ed in the half-life (t1/2) with increasing dose and only a slightly mo re than proportional increase in the area under the concentration-time curve (AUC) occurring with increasing dose. A doubling in dose result ed in a 2.2-fold increase in the AUC. P-1013 and BG were also given i. v., p.o. and i.p. to female nu/nu-BALB/cABom mice and male Wistar rats . A high degree of bioavailability was found in both species, with 55- 100% of the delivered dose being absorbed. Deuteration of BG does not seem to alter its bioavailability, as we found the same bioavailabilit y for P-1013 as for BG. We conclude that the pharmacokinetics of P-101 3 does not prevent its use as a cancer treatment drug given orally.