CORRELATION BETWEEN STUDIES IN VITRO AND IN VIVO IN DRUG METABOLISM/DRUG INTERACTION STUDIES IN THE DRUG DEVELOPMENT PROCESS: STUDIES IN VITRO
TECHNIQUES AND APPROACHES FOR STUDIES IN VITRO OF DRUG METABOLISM AND DRUG INTERACTIONS
CORRELATION BETWEEN STUDIES IN VITRO AND IN VIVO
A complete understanding of the relationship between metabolism in vitro and in vivo is still emerging. Strong correlations have been documented between well-conducted studies in vitro and in vivo, but considerable effort is necessary before complete validation of these correlations is obtained, including an appreciation for whatever limits may exist for the correlations. When a difference arises between findings in vitro and in vivo, the results in vivo should always take precedence over studies in vitro. In many cases, however, studies in vitro, which are inexpensive and readily carried out, will serve as an adequate screening mechanism that can rule out the importance of a metabolic pathway and make in vivo testing unnecessary. If investigations in vitro suggest that the answer to the question “Does CYP450 2D6 metabolize this drug?” is “no,” clinical studies to identify the impact of the slow metabolizer phenotype or to study the effect of CYP450 2D6 inhibitors will not be needed.
Because studies in vitro, however, cannot adequately define the importance of a metabolic pathway, if the in vitro study answer is “yes,” additional clinical studies will be important to answer whether CYP450 2D6 is clinically important to the elimination of the drug.
Additional information also may be necessary to identify which inhibitors, if any, affect metabolism in vivo significantly. For example, although a drug may be extensively metabolized in vitro, a mass balance study in vivo may demonstrate that metabolism is less important than urinary or biliary excretion. In addition, inhibition studies often will not be definitive in vitro unless only a relatively low degree of inhibition is present, with intermediate to high degrees of inhibition needing subsequent clinical confirmation. In this setting, inhibition of metabolic pathways will not have a clinical impact except for patients with severe impairment of excretory function, and the effect of induction on elimination will be limited.
In general, if there is some, but not a large, effect in vitro, predicting the effect in vivo will be difficult. Experiments in vitro should be conducted at concentrations similar to the relevant concentration in vivo. As previously noted for chemical inhibition studies, different pathways may be affected at various concentrations. This may be difficult to determine, however, when the interaction occurs in the gut.
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