๐ ็ธฝ็ฎ้ ๏ฝ ๐ ่ฑๆๅๆ๏ผๆฌ็ฏ๏ผ ๏ฝ ๐ ๅฎๆด็ฟป่ญฏ ๏ฝ โญ ็ฒพ่ฏ็ญ่จ
LEVELS OF EVIDENCE
Drug interaction literature is often confusing due to poorly substantiated claims. This confusion occurs as a result of inaccurate or cursory evaluations of published cases or inappropriate extrapolations from the literature. Metabolic drug interactions are a major source of potential clinical problems, but their investigation during drug development is often incomplete. In vitro studies give very accurate data on the interactions of drugs with selective CYP isozymes, but their interpretation in the clinical context is difficult. Although in vitro systems have been developed to test the effects of certain drugs on the metabolism of other drugs, these systems may not accurately predict the effect in patients receiving drugs with complex metabolism. In addition, problems with the detection of adverse events after a drug has been released arise mainly because such events are rare. It takes a surveillance system with a high degree of sensitivity to detect such problems.
Furthermore, most in vivo and in vitro studies of drug interactions evaluate two-drug regimens, and the results may not apply to the multidrug regimens used clinically. This is especially true for a regimen consisting of three or more drugs with opposing effects on CYP3A4 metabolism. The lack of studies of multiple drug interactions provides little assistance to the prescribing physician, who is left to rely on adverse events or treatment failure to demonstrate whether an interaction has occurred. In addition, the design of in vivo studies is sometimes poor (choice of prototype substrate, doses, schedule of administration, number of volunteers), with the risk of minimizing the real potential for interaction. To link in vitro and in vivo studies, several authors have suggested using extrapolation techniques, based on the comparison of in vitro inhibition data with the active in vivo concentrations of the inhibitor. However, the lack of knowledge with regard to one or several important parameters, such as the role of metabolites and intrahepatocyte accumulation, often limits the ability to make safe and accurate predictions.
The uncertainty and inaccuracy of predicting the extent and duration of in vivo drug interactions currently stems from a lack of definitive models by which to assess likely substrate and inhibitor concentrations at the active site of metabolism. Additional issues contributing to the uncertainty of predicting drug interactions include assumptions of the contribution of presystemic drug extraction and the effect of inhibitors on the processes involved. Therefore, these methods are useful for complementing in vivo studies and helping to design clinically relevant in vivo studies, but in the near future they will not totally replace in vivo investigations.