TY - JOUR
T1 - An excretion balance and pharmacokinetic study of the novel anticancer agent E7070 in cancer patients
AU - van den Bongard, H. J. G. Desirée
AU - Pluim, Dick
AU - Rosing, Hilde
AU - Nan-Offeringa, Lianda
AU - Schot, Margaret
AU - Ravic, Miroslav
AU - Schellens, Jan H. M.
AU - Beijnen, Jos H.
PY - 2002
Y1 - 2002
N2 - E7070 is a novel sulfonamide anticancer agent that arrests the G1/S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics of the drug. The objective of this study was to quantify the excretion of E7070 and the metabolite 1,4-benzene-sulfonamide (M1) in cancer patients. E7070 (1000 mg) radiolabeled by 14C in the benzene disulfonamide moiety (cohort 1, n=6) or in the indole moiety (cohort 2, n=7) was i.v. infused over 1 h. The levels of radioactivity in plasma, red blood cells, urine and feces were determined by liquid scintillation counting, and the E7070 and M1 concentrations in plasma, urine and feces were determined by coupled liquid chromatography-tandem mass spectrometry (LC/ESI-MS/MS). In plasma, the mean area under the concentration-time curve (AUC) based on radioactivity measurements (32.5 and 28.9 h · mM in cohorts 1 and 2, respectively) was substantially higher than the mean AUC of E7070 (3.8 h · mmol/l) and M1 (0.1 h · mmol/l) in all patients. The excretion of radioactivity (mean ± SD) as a percentage of administered radioactivity was higher in urine [63.7 ± 9.8% (cohort 1) and 61.5 ± 5.5% (cohort 2)] than in feces [22.7 ± 2.6% (1) and 21.1 ± 3.1% (2)] during a mean collection period of 11 days. In both cohorts, the contribution of urinary and lecal recovery of E7070 (2.3 and 2.7%, respectively) and M1 (5.3 and 5.1%, respectively) was low. Subsequent HPLC analysis with online radioisotope detection of urine showed that the high radioactivity levels are caused by compounds other than E7070 and M1. The major metabolite is formed by glucuronidation of a hydroxylated metabolite of E7070. In conclusion, the excretion of the benzene sulfonamide and the indole moieties of E7070 was the same with a higher renal than gastrointestinal excretion. E7070 is extensively converted into currently unidentified metabolites. Glucuronidation is a major metabolic pathway. © 2002 Lippincott Williams & Wilkins.
AB - E7070 is a novel sulfonamide anticancer agent that arrests the G1/S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics of the drug. The objective of this study was to quantify the excretion of E7070 and the metabolite 1,4-benzene-sulfonamide (M1) in cancer patients. E7070 (1000 mg) radiolabeled by 14C in the benzene disulfonamide moiety (cohort 1, n=6) or in the indole moiety (cohort 2, n=7) was i.v. infused over 1 h. The levels of radioactivity in plasma, red blood cells, urine and feces were determined by liquid scintillation counting, and the E7070 and M1 concentrations in plasma, urine and feces were determined by coupled liquid chromatography-tandem mass spectrometry (LC/ESI-MS/MS). In plasma, the mean area under the concentration-time curve (AUC) based on radioactivity measurements (32.5 and 28.9 h · mM in cohorts 1 and 2, respectively) was substantially higher than the mean AUC of E7070 (3.8 h · mmol/l) and M1 (0.1 h · mmol/l) in all patients. The excretion of radioactivity (mean ± SD) as a percentage of administered radioactivity was higher in urine [63.7 ± 9.8% (cohort 1) and 61.5 ± 5.5% (cohort 2)] than in feces [22.7 ± 2.6% (1) and 21.1 ± 3.1% (2)] during a mean collection period of 11 days. In both cohorts, the contribution of urinary and lecal recovery of E7070 (2.3 and 2.7%, respectively) and M1 (5.3 and 5.1%, respectively) was low. Subsequent HPLC analysis with online radioisotope detection of urine showed that the high radioactivity levels are caused by compounds other than E7070 and M1. The major metabolite is formed by glucuronidation of a hydroxylated metabolite of E7070. In conclusion, the excretion of the benzene sulfonamide and the indole moieties of E7070 was the same with a higher renal than gastrointestinal excretion. E7070 is extensively converted into currently unidentified metabolites. Glucuronidation is a major metabolic pathway. © 2002 Lippincott Williams & Wilkins.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0036746940&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/12394264
U2 - https://doi.org/10.1097/00001813-200209000-00004
DO - https://doi.org/10.1097/00001813-200209000-00004
M3 - Article
C2 - 12394264
SN - 0959-4973
VL - 13
SP - 807
EP - 814
JO - Anti-Cancer Drugs
JF - Anti-Cancer Drugs
IS - 8
ER -