In vitro and in vivo kinetic interactions of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid with thalidomide and diclofenac.
BACKGROUND
Previous studies have demonstrated that coadministration of L-thalidomide with the novel antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) results in an increased area under the plasma concentration-time curve (AUC) of DMXAA, suggesting an explanation for the observed increase in the antitumour activity. The aims of this study were to investigate the effects of L-thalidomide on the in vitro metabolism of DMXAA in mouse and human liver microsomes using diclofenac as positive control, to examine the effects of L-thalidomide and diclofenac on the plasma protein binding of DMXAA in vitro, and to investigate whether the in vivo interactions can be predicted from in vitro data, particularly in humans.


METHODS
Mouse and human liver microsomes were used to investigate the effects of L-thalidomide and diclofenac on DMXAA metabolism. The resulting in vitro data were extrapolated to predict in vivo changes in DMXAA, which were then compared with the results of in vivo mouse pharmacokinetic interaction studies. The protein binding of DMXAA in mouse and human plasma was determined using ultrafiltration followed by HPLC.


RESULTS
Diclofenac at 100 microM caused significant inhibition of glucuronidation (> 70%) and 6-methylhydroxylation (> 54%) of DMXAA in mouse and human liver microsomes. In vivo diclofenac (100 mg/kg i.p.) resulted in a 24% and 31% increase in the plasma DMXAA AUC, and a threefold increase in T1/2 (P < 0.05) in male and female mice, respectively. In contrast, L-thalidomide at 100 microM had no inhibitory effect on DMXAA metabolism in vitro in either species, except for a decrease of about 25% in 6-methylhydroxylation in mice. L-Thalidomide at 500 microM resulted in further significant decreases in 6-methylhydroxylation in mice (30-60%) and human (30%) microsomes. Coadministration of L-thalidomide in male mice resulted in a 23% increase in DMXAA AUC and a twofold increase in T1/2 (P < 0.05). Neither L-thalidomide nor diclofenac at 50 or 500 microM had any significant effect on the in vitro plasma protein binding of DMXAA (500 microM) in mouse or human plasma. Based on our in vitro inhibition studies, we predicted a 20% increase in DMXAA AUC in mice with concomitant diclofenac, but little or no effect (< 5%) with L-thalidomide.


CONCLUSIONS
Both L-thalidomide and diclofenac increased the plasma DMXAA AUC in mice. In the case of diclofenac, this appeared to be due to direct competitive inhibition of DMXAA metabolism, but this mechanism does not appear to be appropriate for L-thalidomide. From the in vitro human inhibition studies, it appears unlikely that concurrent diclofenac will cause an increase in the plasma AUC of DMXAA in patients. However, the effect of L-thalidomide on DMXAA could not be readily predicted from the in vitro data. Our study demonstrated that a predictive model based on direct inhibition of metabolism is appropriate for diclofenac-DMXAA interactions, but is inappropriate for the prediction of L-thalidomide-DMXAA interactions in mice and humans in vivo.
Zhou
S
S
Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, Private Bag 92019, Auckland, New Zealand.
Paxton
J W
JW
Kestell
P
P
Tingle
M D
MD
Ching
L M
LM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004008:Diclofenac / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D013723:Teratogens / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013792:Thalidomide / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014966:Xanthenes / Q000493:pharmacokinetics* / Q000494:pharmacology*; D044004:Xanthones
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001798:Blood Proteins; D013723:Teratogens; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; D004008:Diclofenac; D013792:Thalidomide