Effect of gastric pH on the relative oral bioavailability and pharmacokinetics of temozolomide

Purpose: Temozolomide is an imidazotetrazine alkylating agent which undergo es chemical conversion at physiological pH to the active species 5-(3-methy ltriazene-1-yl)imidazole-4-carboxamide (MTIC) but is stable at acid pH. Thi s study evaluated the effect of an increase in gastric pH, through the use of ranitidine, on the oral bioavailability and plasma pharmacokinetics of t emozolomide and MTIC. Methods: Fifteen patients with advanced cancer were e nrolled of which 12 were evaluable, all of whom had pharmacokinetic blood s ampling. 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 Heidelbe rg capsule system. Results: Following the administration of ranitidine ther e was a rise in gastric pH by 1-2 pH units over the duration of the study p eriod (pH range 2.2-5.2 without ranitidine and 3.5-6.0 with ranitidine). Th ere was no difference in the pharmacokinetic parameters of temozolomide or MTIC with or without the concomitant administration of ranitidine. There wa s however, a lower C-max for temozolomide and MTIC for patients receiving r anitidine on day 1 and 2 versus day 4 and 5. Temozolomide was rapidly absor bed [time to maximum plasma concentration (t(max)) 1:8 h] and eliminated [e limination half-life (t(1/2)) 1.8 h] and MTIC followed a similar pattern wi th a t(max) of 1.9 h and a t(1/2) of 1.9 h. Overall, the AUC of the MTIC re presented about 2-4% of the AUC for temozolomide.