Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer.
The purpose of this study is to characterize the absorption, metabolism, and excretion of carbon 14-labeled temozolomide (14C-TMZ) administered p.o. to adult patients with advanced solid malignancies. On day 1 of cycle 1, six patients received a single oral 200-mg dose of 14C-TMZ (70.2 microCi). Whole blood, plasma, urine, and feces were collected from days 1-8 and on day 14 of cycle 1. Total radioactivity was measured in all samples. TMZ, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), and 4-amino-5-imidazole-carboxamide (AIC) concentrations were determined in plasma, and urine and plasma samples were profiled for metabolite/degradation products. Maximum TMZ plasma concentrations were achieved between 0.33 to 2 h (mean, 1.2 h), and half-life, apparent volume of distribution, and oral clearance values averaged 1.9 h, 17 liters/m2, and 104 ml/min/m2, respectively. A first-order absorption, one-compartment linear model, which included first-order formation of MTIC from TMZ and elimination of MTIC via degradation to AIC, and a peripheral distribution compartment for AIC, adequately described the plasma TMZ, MTIC, and AIC concentrations. MTIC systemic clearance was estimated to be 5384 ml/min/m2, and the half-life was calculated to be 2.5 min. Metabolite profiles of plasma at 1 and 4 h after treatment showed that 14C-derived radioactivity was primarily associated with TMZ, and a smaller amount was attributed to AIC. Profiles of urine samples from 0-24 h revealed that 14C-TMZ-derived urinary radioactivity was primarily associated with unchanged drug (5.6%), AIC (12%), or 3-methyl-2,3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxyl ic acid (2.3%). The recovered radioactive dose (39%) was principally eliminated in the urine (38%), and a small amount (0.8%) was excreted in the feces. TMZ exhibits rapid oral absorption and high systemic availability. The primary elimination pathway for TMZ is by pH-dependent degradation to MTIC and further degradation to AIC. Incomplete recovery of radioactivity may be explained by the incorporation of AIC into nucleic acids.
The Johns Hopkins Oncology Center, Baltimore, Maryland 21287, USA. sbaker@saci.org
S D
SD
Baker
M
M
Wirth
P
P
Statkevich
P
P
Reidenberg
K
K
Alton
S E
SE
Sartorius
M
M
Dugan
D
D
Cutler
V
V
Batra
L B
LB
Grochow
R C
RC
Donehower
E K
EK
Rowinsky
D000042:Absorption; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000620:Aminoimidazole Carboxamide / Q000097:blood / Q000493:pharmacokinetics; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D000620:Aminoimidazole Carboxamide; D003606:Dacarbazine; C010243:5-(3-methyl-1-triazeno)imidazole-4-carboxamide; D000077204:Temozolomide