[Clinical pharmacology of nucleoside analogues].
The drugs concerned by this review are cytarabine (ara-C), gemcitabine and fludarabine. Seventy-eighty per cent of a dose of ara-C are excreted under the form of ara-U (main metabolite). Plasma concentrations of ara-C are not related to drug pharmacodynamics (response to treatment) in contrast to intracellular levels of ara-CTP (active metabolite) which are associated with cytotoxic activity. Gemcitabine is able to autoactivate its own mechanism of action. Gemcitabine is characterized by a short half-life of elimination (15-20 min) and plasma pharmacokinetics of the drug are not linked to pharmacodynamics. Prolonged administration of gemcitabine is pharmacokinetically and pharmacologically justified and should deserve more intense clinical investigations. Total body clearance of F-ara-A (main circulating metabolite of fludarabine) is linked to creatinine clearance and drug-related neutropenia are more frequent in patients with creatinine clearance below 50 mL/min. So far there are no relationships between intracellular levels of F-ara-CTP and response to treatment.
Milano
Gérard
G
Centre Antoine-Lacassagne, 33, avenue de Valombrose, 06189 Nice.
Chamorey
Anne-Laure
AL
Thyss
Antoine
A
D000963:Antimetabolites / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001711:Biotransformation; D003561:Cytarabine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003564:Cytidine Deaminase / Q000378:metabolism; D003844:DCMP Deaminase / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003842:Deoxycytidine Kinase / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D011355:Prodrugs / Q000493:pharmacokinetics; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000093542:Gemcitabine
D000963:Antimetabolites; D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D011355:Prodrugs; D003561:Cytarabine; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D003844:DCMP Deaminase; D003564:Cytidine Deaminase; D014740:Vidarabine; C024352:fludarabine; D000093542:Gemcitabine