A pharmacokinetics approach to drug interactions.

When drug interference is suspected, a pharmacokinetic study is safer for patients than a large-scale toxicology study. This is particularly true if increased exposition to a drug can lead to cumulative, life-threatening toxicity, like in the case of the cardiotoxic anthracyclines. Patients in a pharmacokinetic study are exposed to a single administration of the combination. If drug and metabolites analysis reveals altered drug disposition, these patients can be subsequently treated with adjusted dosages. Induction or inhibition of P450s and other drug-metabolizing enzymes can alter the disposition of xenobiotics and consequently the serum levels of unchanged drugs and metabolites dependent by these enzyme systems. Modern analytical techniques, especially HPLC or capillary electrophoresis coupled to mass spectrometry, although expensive can easily deal with qualitative and quantitative determinations of a complex metabolic pattern. The ATP-binding cassette (ABC) transporter superfamily contains membrane proteins that translocate a wide variety of substrates across extra- and intracellular membranes. Intrinsic and acquired multidrug resistance (MDR) in many human cancers may be due to over-expression of the multidrug transporter P-glycoprotein (Pgp), which is encoded by the mdr1 gene. Pgp is also a major transporter in tissues responsible for the excretion of xenobiotics. Modulation of Pgp in tumors by co-administration of Pgp inhibitors is likely to be accompanied by altered Pgp function in normal tissues, with pharmacokinetic interactions manifesting as inhibition of the disposition of MDR-related cytotoxins and increased systemic toxicity. Traffic ATPases are also involved in drug absorption from the gastro-intestinal tract, and the percentage of the drug which is absorbed after oral treatment can drastically increase if a specific inhibitor is co-administered. Pharmacokinetic evaluations are therefore required when the inhibition of transporters is experimented in order to overcome the resistance to anticancer drugs. Two or more different drugs may also bind to the same site on plasma proteins. Thus, administration of a second drug may significantly affect the binding of the first drug. For instance, the anticoagulant, warfarin at its therapeutic concentration is 97.4% bound. Co-administration of the nonsteroidal antiinflammatory drug phenylbutazone decreases bound warfarin to 92%. A 3-fold increase in free warfarin can be observed, with a consequent increase of the anticoagulant effect. When this kind of interaction is suspected, the pharmacokinetic evaluation must be based on analytical techniques that can differentiate bound and free drug.