The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (TomudexTM) in a nonhuman primate model

  title={The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (TomudexTM) in a nonhuman primate model},
  author={Brigitte C. Widemann and Frank M. Balis and Karen S. Godwin and Cynthia M. McCully and Peter C. Adamson},
  journal={Cancer Chemotherapy and Pharmacology},
Purpose: Raltitrexed (Tomudex™), ZD1694) is a novel quinazoline folate analog that selectively inhibits thymidylate synthase. Intracellularly, raltitrexed is polyglutamated to its active form which can be retained in cells for prolonged periods. The pharmacokinetics of raltitrexed in plasma and cerebrospinal fluid (CSF) were studied in a nonhuman primate model. Methods: Animals received 3 mg/m2 (n= 1), 6 mg/m2 (n= 3), or 10 mg/m2 (n= 3) i.v. over 15 min, and frequent plasma samples were… 

Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates

The CSF penetration of pemetrexed was less than 2%, suggesting that it should be used in conjunction with other CNS preventive strategies when used in the treatment of malignancies with a predilection for CNS or leptomeningeal metastases.

Clinical and Preclinical Pharmacokinetics of Raltitrexed

It has not been possible to establish strong correlations between the plasma pharmacokinetics of raltitrexed and toxicity, and the cellular pharmacokinetic patterns may be more predictive, but delayed administration of folinic acid can assist in the recovery of animals from antiproliferative toxicity.

Study on brain targeting of raltitrexed following intranasal administration in rats

Results showed that antineoplastic RTX could be directly transported into the brain via the olfactory pathway in rats.

Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors: the Children's Oncology Group.

Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults, and the recommended dose for phase II studies is 1,910 mg/m2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.

Identification of novel thymidylate synthase therapeutics for treatment of H.pylori

Hindering the thyX activi ty decreases the DNA replication, pyrimidine metabolism necessary for proliferation of H. pylori, in turn reduces the progression of pathogenesis leading to stomach cancer.

Electrochemistry Study of Antineoplastic Raltitrexed Oxidation Mechanism and its Interaction with DNA

Raltitrexede (RTX) is a folate analogue that belongs to the antimetabolites family and has antineoplastic activity correlated to inhibition of the thymidylate synthase (TS) enzyme. This study

The Role of Folate Transport in Antifolate Drug Action in Trypanosoma brucei*

RNAi knockdown of TbFT1–3 substantially reduced folate transport into trypanosomes and reduced the parasite's susceptibly to the classical antifolates methotrexate and raltitrexed, and Tb FT1-3 loss-of-function is a mechanism of antifolate drug resistance.

Determination of raltitrexed in human plasma by high performance liquid chromatography-electrospray ionization-mass spectrometry.


This comprehensive study summarizes the different deriva tives of substituted quinazolinone along with their chem istry, biological evaluation, and their major applic ations in the field of medicine to provide base for the future research work regarding modifications in quinzolinone moiety and its implementation in drug discovery and drug development.

Synthesis and Evaluation of α-Glucosidase and Pancreatic Lipase Inhibition by Quinazolinone-Coumarin Hybrids

A new series of 2-substituted quinazolin-4(3H)-one derivatives including coumarin nucleus has been synthesized and screened for their lipase and α-glucosidase inhibition properties. Among the



Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models.

Although it has not been possible to measure individual polyglutamated forms of ZD1694, the radioimmunoassay provides a convenient means of assessing total drug levels in tissues and is currently the only method suitable for measuring the extent of drug retention in normal tissue and tumour biopsies obtained from patients treated with ZD 1694.

The role of the reduced-folate carrier and metabolism to intracellular polyglutamates for the activity of ICI D1694.

The results of short-exposure assays and in situ TS assays confirms that 7-methylation largely prevents the formation of a retained drug-form (polyglutamates), continuous exposure being necessary to maintain TS inhibition and cause a cytotoxic effect after removal of extracellular drug.

Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors.

  • S. ClarkeJ. Hanwell I. Judson
  • Medicine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 1996
A phase I clinical and pharmacologic study of ZD1694, a new folate-based thymidylate synthase (TS) inhibitor, in patients with advanced malignancy found a linear relationship between dose and both the area under the concentration-time curve (AUC) and maximum concentration (Cmax), but no clear association between these parameters and response or toxicity.

ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study.

The L1210:1565 cell line, which has greatly impaired reduced-folate/methotrexate transport and thus is resistant to methotrexate, was significantly cross-resistant to ICI D1694, suggesting that ICID1694 is dependent on this uptake mechanism for good cytotoxic potency in L 1210 cells.

Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines.

Four cell lines, the mouse L1210 leukaemia, the human W1L2 lymphoblastoid and two human ovarian cells, were made resistant to ZD1694 by continual exposure to incremental doses of the drug by finding cross-resistance was found to those compounds known to be active through polyglutamation.

ZD1694: A novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. Tomudex Colorectal Study Group.

Tomudex has an acceptable toxicity profile and a convenient dosing schedule (single intravenous injection every 3 weeks) and thus appears to offer real potential as a novel agent for the treatment of patients with advanced CRC.

'Tomudex' (ZD1694): a novel thymidylate synthase inhibitor with clinical antitumour activity in a range of solid tumours. 'Tomudex' International Study Group.

'Tomudex' represents the successful culmination of a rational drug design programme, and shows promise as a new cytotoxic for the treatment of colorectal cancer.

Pharmacokinetics of 9-cis-retinoic acid in the rhesus monkey.

The studies in the Rhesus monkey suggest that declines in plasma concentrations of 9-cis-retinoic acid as a result of its repeat administration at doses up to 100 mg/m2 will not occur, suggesting that isomerization to all-trans-retinosic acid is not a major metabolic pathway.

The history of the development and clinical use of CB 3717 and ICI D1694.

The antifolate thymidylate synthase inhibitors represent an exciting area in new drug development and show that with an understanding of the structural basis for toxicity, new drugs can be

A rhesus monkey model for continuous infusion of drugs into cerebrospinal fluid.

This new rhesus monkey model has applications both for the development of continuous intraventricular infusion as a therapeutic approach for the treatment of meningeal cancers in humans and as a research tool to study the distribution and elimination of drugs from the CSF.