Clinical phase I and pharmacology study of gemcitabine (2', 2'-difluorodeoxycytidine) administered in a two-weekly schedule.
Gemcitabine (dFdC) was tested in a Phase I trial at 14 doses (40-5700 mg/m(2)), administered every 2 weeks as a (1/2) -h infusion to 52 patients with refractory solid cancer. Gemcitabine and its deaminated metabolite difluorodeoxyuridine (dFdU), measured with HPLC, reached plasma peak levels of 2-3 microM at 40 mg/m(2) which increased to 512 microM at 5700 mg/m(2). Gemcitabine was eliminated rapidly with a t(1/2) beta of 2.3-15.8 min in the 40-5700 mg/m(2) dose range, with one exception of 38 min at 4500 mg/m(2) . dFdU was still present at a plateau of +/- 20 microM from 4-24 h at doses >960 mg/m(2). Up to 3650 mg/m(2) linear pharmacokinetics were observed for gemcitabine, while those for dFdU were linear over the whole range. Gemcitabine clearance varied between 1.5-12.6 l/min and was 1.5-fold higher in males than in females (p= 0.024); its volume of distribution was 45.2-248 l. In lymphocytes peak levels of the active metabolite dFdCTP were 100-380 pmol/10( 6 )cells in the first course. Apparently a plateau was reached which was confirmed by incubation of white blood cells with increasing gemcitabine concentrations up to 500 microM, reaching a plateau of about 350 pmol/10(6 )cells; in contrast in cancer cells this concentration dependence did not exist and accumulation reached about 1590 pmol/10( 6 )cells. In tumors isolated from patients treated with gemcitabine dFdCTP reached about 70 pmol/g wet weight. Gemcitabine itself was eliminated only to a limited extent in the urine, but dFdU was eliminated almost completely in the urine in the first 24 h (51-92%). In conclusion, dFdC was rapidly eliminated in contrast to dFdU, which was present for at least 18 h, as well as dFdCTP in lymphocytes.
Peters
G J
GJ
Department of Medical Oncology, VU University Medical University, Amsterdam, The Netherlands. gj.peters@vumc.nl
Clavel
M
M
Noordhuis
P
P
Geyssen
G J
GJ
Laan
A C
AC
Guastalla
J
J
Edzes
H T
HT
Vermorken
J B
JB
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine