Flavopiridol metabolism in cancer patients is associated with the occurrence of diarrhea.
Flavopiridol, a cyclin-dependent kinase inhibitor currently undergoing clinical evaluation, has a dose-limiting toxicity of diarrhea. Preclinical data on flavopiridol metabolism indicate that flavopiridol undergoes hepatic glucuronidation. The purpose of this study is to evaluate whether the occurrence of diarrhea is related to the systemic glucuronidation of flavopiridol. Parent drug and metabolite concentrations in plasma were measured by high-pressure liquid chromatography in 22 metastatic renal cancer patients treated on a Phase II trial of 50 mg/m2/day of flavopiridol administered every 2 weeks as a 72-h continuous infusion. Pharmacokinetics of flavopiridol and its glucuronide were assessed during the first cycle at 23, 47, and 71 h during the infusion. Flavopiridol concentrations at 23, 47, and 71 h were 389 nM (296-567 nM), 412 nM (297-566 nM), and 397 nM (303-597 nM) [median (interquartile range)], respectively. Flavopiridol glucuronide reached a plateau of 358 nM (196-553 nM) at 47 h. Metabolic ratios of flavopiridol glucuronide:flavopiridol at 71 h showed an apparent bimodal distribution with an antimode of 1.2. Thirteen patients experienced diarrhea and had lower metabolic ratios [0.72 (0.53-0.86)] than patients without diarrhea [2.24 (1.76-2.3); P = 0.002]. Eight of 11 extensive glucuronidators (ratio > 1.2) did not develop diarrhea, whereas 10 of 11 poor glucuronidators (ratio < 1.2) developed diarrhea (P = 0.008). The glucuronidation of flavopiridol is apparently polymorphic, suggesting a genetic etiology. The systemic glucuronidation of flavopiridol is inversely associated with the risk of developing diarrhea.
Innocenti
F
F
Department of Medicine, University of Chicago, Illinois 60637, USA.
Stadler
W M
WM
Iyer
L
L
Ramírez
J
J
Vokes
E E
EE
Ratain
M J
MJ
D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000378:metabolism* / Q000493:pharmacokinetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism*; D017322:Clinical Trials, Phase II as Topic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D003967:Diarrhea / Q000139:chemically induced*; D005260:Female; D005419:Flavonoids / Q000009:adverse effects* / Q000378:metabolism* / Q000493:pharmacokinetics; D005965:Glucuronates / Q000009:adverse effects / Q000096:biosynthesis / Q000097:blood; D006801:Humans; D007262:Infusions, Intravenous; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000009:adverse effects* / Q000378:metabolism* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D005419:Flavonoids; D005965:Glucuronates; D010880:Piperidines; C077990:alvocidib; D018844:Cyclin-Dependent Kinases