The bioavailability and dose dependency of the deuterated anti-tumour agent 4,6-benzylidene-d1-D-glucose in mice and rats.

Abstract

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-benzylidene-d1-D-glucose (P-1013). In this study we compared the bioavailability 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 pharmacokinetics. Pharmacokinetics were studied by analysing plasma samples using reversed-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 bioavailability was more than 50% for all doses. The results also indicate that P-1013 shows linear pharmacokinetics, with no change being observed in the half-life (t1/2) with increasing dose and only a slightly more than proportional increase in the area under the concentration-time curve (AUC) occurring with increasing dose. A doubling in dose resulted 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 bioavailability for P-1013 as for BG. We conclude that the pharmacokinetics of P-1013 does not prevent its use as a cancer treatment drug given orally.

• Authors: C B Dunsaed, J M Dornish, E O Pettersen
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 35 Issue 6 Pg. 464-70 ( 1995) ISSN: 0344-5704 [Print] Germany
• PMID: 7882455 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• benzylidene glucose
• Deuterium
• Glucose

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Biological Availability
• Chromatography, High Pressure Liquid
• Deuterium (metabolism)
• Dose-Response Relationship, Drug
• Drug Evaluation
• Female
• Glucose (administration & dosage, analogs & derivatives, pharmacokinetics, therapeutic use)
• Half-Life
• Injections, Intraperitoneal
• Injections, Intravenous
• Isotope Labeling
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Rats
• Rats, Wistar
• Structure-Activity Relationship