Preclinical prediction of factors influencing the elimination of 5,6-dimethylxanthenone-4-acetic acid, a new anticancer drug.
The glucuronidation of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a newly developed anticancer drug, was investigated in vitro to determine factors likely to affect the elimination of this compound in patients. Human liver microsomal DMXAA glucuronidation followed Michaelis-Menten kinetics, with a mean apparent Km of approximately 100 microM. Two cDNA-expressed UGT isoforms, UGT1*02 and UGT2B7, had the capacity to glucuronidate DMXAA, although comparative kinetic and inhibitor studies were more consistent with a greater contribution of UGT2B7 to the human hepatic reaction. Microsomal DMXAA glucuronide formation was screened for inhibition by drugs known to be eliminated by glucuronidation. Of the drugs screened, significant inhibition was observed with diclofenac, epirubicin, indomethacin, R,S-ketoprofen, lorazepam, S-naproxen, oxazepam, and temazepam; apparent Ki values ranged from 9.5-318 microM. These values are substantially above unbound concentrations of the individual drugs achieved in vivo. DMXAA glucuronide was found to be unstable at physiological pH values, and the rate of degradation was marginally increased in the presence of albumin. Taken together, these data indicate that the kinetics of DMXAA glucuronidation in vivo are likely to be linear and unaffected by the coadministration of most glucuronidated drugs, but plasma DMXAA clearance may be decreased in patients with renal dysfunction. This study illustrates the utility of in vitro techniques for the prediction of potential drug interactions and other dispositional characteristics of newly developed anticancer drugs before their administration to patients.
Miners
J O
JO
Department of Clinical Pharmacology, Flinders Medical Centre, Bedford Park SA, Australia.
Valente
L
L
Lillywhite
K J
KJ
Mackenzie
P I
PI
Burchell
B
B
Baguley
B C
BC
Kestell
P
P
D000970:Antineoplastic Agents / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D014966:Xanthenes / Q000378:metabolism*; D044004:Xanthones
D000970:Antineoplastic Agents; D005965:Glucuronates; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan