Effect of gastric pH on the relative oral bioavailability and pharmacokinetics of temozolomide.
OBJECTIVE
Temozolomide is an imidazotetrazine alkylating agent which undergoes chemical conversion at physiological pH to the active species 5-(3-methyltriazene-1-yl)imidazole-4-carboxamide (MTIC) but is stable at acid pH. This study evaluated the effect of an increase in gastric pH, through the use of ranitidine, on the oral bioavailability and plasma pharmacokinetics of temozolomide and MTIC.


METHODS
Fifteen patients with advanced cancer were enrolled of which 12 were evaluable, all of whom had pharmacokinetic blood sampling. Each patient received temozolomide 150 mg m(-2) day(-1) for 5 days in cycle 1 and also received ranitidine 150 mg every 12 h either on days 1 and 2 or days 4 and 5. Gastric pH was monitored by the use of the Heidelberg capsule system.


RESULTS
Following the administration of ranitidine there was a rise in gastric pH by 1-2 pH units over the duration of the study period (pH range 2.2-5.2 without ranitidine and 3.5-6.0 with ranitidine). There was no difference in the pharmacokinetic parameters of temozolomide or MTIC with or without the concomitant administration of ranitidine. There was however, a lower C(max) for temozolomide and MTIC for patients receiving ranitidine on day 1 and 2 versus day 4 and 5. Temozolomide was rapidly absorbed [time to maximum plasma concentration (t(max)) 1.8 h] and eliminated [elimination half-life (t(1/2)) 1.8 h] and MTIC followed a similar pattern with a t(max) of 1.9 h and a t(1/2) of 1.9 h. Overall, the AUC of the MTIC represented about 2-4% of the AUC for temozolomide.
Beale
P
P
Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK. pbeale@canc.rpa.cs.nsw.gov.au
Judson
I
I
Moore
S
S
Statkevich
P
P
Marco
A
A
Cutler
D L
DL
Reidenberg
P
P
Brada
M
M
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005744:Gastric Acid; D005745:Gastric Acidity Determination; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011899:Ranitidine / Q000627:therapeutic use*; D000077204:Temozolomide
D000897:Anti-Ulcer Agents; D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D011899:Ranitidine; D000077204:Temozolomide