Clinical pharmacokinetics of antitumor antifolates.
Antifolate drugs, as a class, have broad-spectrum activity against both hematologic and solid human malignancies. The pharmacokinetics of the classical antifolate methotrexate have been well-defined and pharmacokinetic data can be exploited to reduce the toxicity and enhance the activity of the drug. Methotrexate remains the only anticancer drug for which plasma drug level monitoring is used in routine clinical practice. Recently, novel classical and nonclassical antifolates have been developed that target either specific folate-dependent enzymes (e.g., thymidylate synthase [CB3717, raltitrexed, ZD9331, 1843U89, nolatrexed, AG331], glycinamide ribonucleotide transformylase [lometrexol, LY309887, AG2034] or multiple folate-dependent enzymes (e.g., MTA/LY231514). In the early clinical trials of these agents, a number of pharmacokinetic-pharmacodynamic relationships were identified and it is highly likely that the full therapeutic potential of these new drugs will also require the exploitation of pharmacokinetic data.
Newell
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Cancer Research Unit, Medical School, University of Newcastle, UK.
D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005492:Folic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics; D054833:Isoindoles; D008727:Methotrexate / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics; D013763:Tetrahydrofolates / Q000493:pharmacokinetics; D013876:Thiophenes / Q000493:pharmacokinetics; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D007211:Indoles; D054833:Isoindoles; D011799:Quinazolines; D013763:Tetrahydrofolates; D013876:Thiophenes; C094299:ZD 9331; C079601:1843U89; C045894:lometrexol; C031662:CB 3717; C087748:AG 331; D005492:Folic Acid; D013940:Thymidylate Synthase; C068874:raltitrexed; D008727:Methotrexate