Dose-Dependent Metabolism, Therapeutic Effect, and Toxicity of Anticancer Drugs in Man

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Abstract
Dose-dependent metabolism is seen for a number of anticancer drugs, and they provide examples of several different types of dose-dependent metabolic processes. Arabinosyl cytosine and 5-fluorouracil are drugs whose catabolism is saturated at high doses. Therapeutic response to both drugs has been linked to plasma concentration of parent compound, and a nonlinear dose-response relationships might exist at high doses. L-Alanosine also appears to exhibit saturable metabolism at high doses, and this might be responsible for the rapid onset of L-alanosine toxicity as the dose is increased. Isophosphamide is a drug which requires metabolic activation to exert its biological effect, and saturation of metabolism seen at high dose could lead to a plateau in the dose-response relationship. Thymidine exhibits saturation of metabolism at high doses due in part to product inhibition of metabolism. Product inhibition of metabolism has also been suggested for arabinosyl cytosine. Plasma elimination of thymidine and possible elimination of 6-diazo-5-oxo-L-norleucine exhibit characteristics of a dose-dependent "memory" effect. Dose-dependent metabolism of methotrexate is unusual in that formation of the presumed toxic metabolite increases with increase in dose and is associated with a qualitative change in the pattern of drug toxicity at high compared to low doses of drug. The relationship between dose and toxicity of drugs and other foreign compounds is poorly understood in man. Anticancer drugs are one of the few classes of compounds where the relationship of toxicity to dose is reasonably well documented in human subjects. Saturation of metabolism leading to dose-dependent pharmacokinetics occurs with several anticancer drugs, and different types of dose-dependent metabolism have been covered in this review. An attempt has been made to show how dose-dependent metabolism of anticancer drugs might relate to their toxicity. Principles of dose-dependent toxicity seen with anticancer drugs might usefully be applied to other classes of compounds, particularly compounds exhibiting cytotoxicity but also other forms of toxicity. Dose-dependent metabolism could also be important in determining the therapeutic effect of anticancer drugs, and application of principles of dose-dependent metabolism to the development of new chemotherapeutic regimens migh lead to more effective cancer chemotherapy.