Pharmacokinetic considerations on resistance to anticancer drugs.
A model framework is discussed for a quantitative description of intercompartment drug transport in terms of individual processes involved. It permits joint consideration of blood flow, membrane transport, binding, and enzyme synthesis. Illustrations are drawn from the pharmacokinetics and pharmacodynamics of methotrexate. Special cases include flow and membrane limitation, and a simple expression is derived to estimate the time required for intracellular drug to reach the concentration of high-affinity binding sites. Transport parameters between blood and cerebrospinal fluid are inferred from new clinical data. Lumbar injection provided a reservoir effect which maintained plasma concentration for a prolonged time compared with intravenous injections.
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D001665:Binding Sites; D001692:Biological Transport; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D008566:Membranes / Q000378:metabolism; D008727:Methotrexate / Q000378:metabolism; D008954:Models, Biological; D013762:Tetrahydrofolate Dehydrogenase / Q000096:biosynthesis
D000970:Antineoplastic Agents; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate