PRECLINICAL APPROACH FOR IDENTIFYING DRUG-INTERACTIONS

Pharmacokinetic drug interactions may be divided into two categories: induction and inhibition of enzymes involved in the metabolism of a dr ug. The induction and inhibition of such enzymes result in decreases o r increases in the blood concentrations of the drug, causing drug effe cts to be altered. Cytochrome P450 (P450 or CYP) is an enzyme responsi ble for the metabolism of a wide variety of drugs, including some anti cancer agents. If a drug with a high affinity to bind to a specific fo rm of P450 is given to a patient in combination with other drugs mainl y metabolized by this enzyme, the former may potentiate the pharmacolo gical actions of the latter by preventing their metabolism and thus in creasing their serum concentration. Alternatively, if a drug inhibits or inactivates essentially all forms of P350 nonspecifically, it may b e possible that the pharmacological effects of other drugs used in com bination with it will be enhanced. CYP3A4 is one of the major forms of P450 in human liver microsomes. In previous studies using human liver microsomes, docetaxel was determined to be metabolized mainly by this isozyme. Thus it was assumed that inducers and inhibitors of CYP3A4 m ight affect the pharmacokinetics of docetaxel. In our studies, adminis tration of dexamethasone, a known inducer of CYP3A, to mice resulted i n decreases in serum docetaxel concentrations. In contrast, ketoconazo le, an inhibitor of CYP3A, is assumed to increase the serum and hepati c concentrations of docetaxel. As an example of a drug which might inh ibit the metabolism of other drugs, we found that bis-aceto-ammine-dic hloro-cyclohexylamine platinum(IV) (JM216), which is currently being d eveloped as a potential anticancer agent, inhibits essentially all maj or forms of P450 present in human liver microsomes. Since its inhibiti on potency is relatively high, careful assessment of the effects of th is drug on the metabolism of other drugs appears to be necessary.