Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 44, Issue 5, pp 389–394 | Cite as

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

  • Philip Beale
  • Ian Judson
  • Sally Moore
  • Paul Statkevich
  • Aliceanne Marco
  • David L. Cutler
  • Pascale Reidenberg
  • Michael Brada
ORIGINAL ARTICLE

Abstract

Purpose: 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 Cmax 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 (tmax) 1.8 h] and eliminated [elimination half-life (t1/2) 1.8 h] and MTIC followed a similar pattern with a tmax of 1.9 h and a t1/2 of 1.9 h. Overall, the AUC of the MTIC represented about 2–4% of the AUC for temozolomide.

Key words Temozolomide MTIC Pharmacokinetics Gastric pH Phase I trial Heidelberg capsule 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • Philip Beale
    • 1
  • Ian Judson
    • 1
  • Sally Moore
    • 1
  • Paul Statkevich
    • 2
  • Aliceanne Marco
    • 2
  • David L. Cutler
    • 2
  • Pascale Reidenberg
    • 2
  • Michael Brada
    • 1
  1. 1.Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UKGB
  2. 2.Plough Research Institute, Kenilworth, NJ, USAUS

Personalised recommendations