Modulation of the pharmacokinetics of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice by thalidomide.
BACKGROUND
5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an investigative drug currently in clinical trial, acts on tumour vasculature through the induction of cytokines. Coadministration of thalidomide, a modulator of cytokine production, potentiates the antitumour activity of DMXAA against the murine Colon 38 carcinoma in mice. We wished to determine whether alteration of the pharmacokinetics of DMXAA by thalidomide could provide an explanation for this potentiation.


RESULTS
Coadministration of thalidomide to Colon 38 tumour-bearing mice significantly (P < 0.05) increased the elimination half-life (t1/2) of DMXAA in plasma (413 micromol/l), liver (132 micromol/l), and spleen (77 micromol/l), and significantly (P < 0.05) increased DMXAA concentrations in Colon 38 tumour tissue (0.25-4.5 h). L-Thalidomide had a greater effect on DMXAA elimination (P < 0.01) than did D-thalidomide or the racemate. Coadministration of thalidomide increased the area under the concentration-time curve (AUC) of DMXAA by 1.8-fold in plasma, liver and spleen, and by 3.0-fold in tumour. Bile from mice given thalidomide and DMXAA contained substantially lower amounts of the glucuronide metabolite of DMXAA (DMXAA-G) than did bile from mice given DMXAA alone.


CONCLUSIONS
Glucuronidation is a major excretory pathway for DMXAA in the mouse. Thalidomide, probably as the L-form, decreases the rate of elimination of DMXAA from plasma, spleen, liver and tumour by altering the rate of glucuronidation. The reduction in the elimination of DMXAA by thalidomide may lead to a selective increase in exposure of tumour tissue to drug, providing a basis for its potentiation of antitumour activity.
Kestell
P
P
Auckland Cancer Society Research Centre, University of Auckland Medical School, New Zealand.
Zhao
L
L
Baguley
B C
BC
Palmer
B D
BD
Muller
G
G
Paxton
J W
JW
Ching
L M
LM
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D003110:Colonic Neoplasms / Q000097:blood / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D051379:Mice; D008810:Mice, Inbred C57BL; D013237:Stereoisomerism; D013792:Thalidomide / Q000494:pharmacology*; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D014966:Xanthenes / Q000097:blood / Q000493:pharmacokinetics*; D044004:Xanthones
D000970:Antineoplastic Agents; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; D013792:Thalidomide