Drug-Drug Interactions by Rodrigues A. D. (ed.)

By Rodrigues A. D. (ed.)

Assisting researchers are expecting drug interactions in a extra actual and potent demeanour, this finished quantity covers each severe point of metabolism-based drug-drug interactions, together with preclinical, medical, toxicological, regulatory, and advertising views through popular idea leaders of their respective fields. completely up to date, the second one version displays key advancements within the box, together with a stronger realizing of the connection among transporters and enzymes in drug metabolism and drug interactions. Formatted to learn the reader, this resource offers worthwhile case examples, consultant enzyme structures, and computer-aided modeling, in addition to 2 hundred necessary tables, equations, drawings, and pictures to elucidate key innovations

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Intrinsic Clearance Like clearance in general, (hepatic) intrinsic clearance is a proportionality constant, in this case between the rate of elimination and unbound concentration within the liver, CuH. That is, CLint ¼ (Rate of elimination)/CuH. Conceptually, it is the value of clearance one would obtain if there were no protein binding or perfusion limitation, and is regarded as a measure of the activity within the cell, divorced from any limitations imposed by events in the perfusing blood. As such, the value of intrinsic clearance is often many orders of magnitude greater than for hepatic blood flow.

For example, although no longer prescribed, the antiinflammatory compound phenylbutazone interacts with many drugs, as is well documented. One in particular is noteworthy here, namely, the interaction with warfarin causing an augmentation of its anticoagulant effect. On investigation, it was found that phenylbutazone not only markedly inhibits many of the metabolic pathways responsible for warfarin elimination, but also displaces warfarin from its major binding protein, albumin, making interpretation of the pharmacokinetic events based on total plasma concentration problematic (13,14).

This effect has several implications. First, the full effects of an interaction may occur long after the inhibitor has been added to the dosage regimen of the affected drug, with the danger that any resulting toxicity may not be associated with the offending drug by either the patient or the clinician. Second, in planning in vivo interaction studies during development, administration of the affected drug may need to be maintained for much longer in the presence of the potential inhibitor than on the basis of the normal half-life of the drug.

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