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a systems approach for tumor pharmacokinetics肿瘤药物动力学的系统方法
A Systems Approach for Tumor Pharmacokinetics
Greg Michael Thurber*, Ralph Weissleder*
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
Abstract
Recent advances in genome inspired target discovery, small molecule screens, development of biological and
nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences
in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of
drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the
development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable
to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for
categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism
of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization,
interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates
determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow,
extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus
macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-
level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should b
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