title: 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.affiliation: Department of Tissue Culture, Institute for Cancer Research, Norwegian Radium Hospital, Montebello, Oslo.
authors.forename: C B
authors.initials: CB
authors.lastname: Dunsaed
authors.forename: J M
authors.initials: JM
authors.lastname: Dornish
authors.forename: E O
authors.initials: EO
authors.lastname: Pettersen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003903:Deuterium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D005947:Glucose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C013844:benzylidene glucose; D003903:Deuterium; D005947:Glucose