The Impact of Infection and Inflammation on Drug Metabolism, Active Transport, and Systemic Drug Concentrations in Veterinary Species

Abstract

Within human medicine, it is recognized that the pharmacokinetics (PK) of many compounds can be altered by the presence of inflammation or infection. Research into the reason for these changes has identified pathways that can influence drug absorption, clearance, and tissue distribution. In contrast, far less is known about these relationships within the framework of veterinary medicine. Rather, most of the PK data generated in veterinary species employs healthy subjects, raising the question of whether these studies are founded on an assumption that healthy animal PK reflect that of the diseased animal population. Accordingly, there is a need to explore the PK changes that might be overlooked in studies that recruit only healthy animals to assesses drug PK. To meet this objective, we surveyed the published literature for studies focusing on the impact of disease on the dose-exposure relationships in food-producing and companion animal species. We found that, consistent with humans and laboratory species, both up-and downregulation of the various cytochrome isoenzymes and/or transporters have occurred in response to an increase in inflammatory mediators. These findings suggest that, as observed in human medicine, the potential for differences in the drug PK in healthy versus animal patients points to a need for acquiring a greater understanding of these changes and how they may influence the dose-exposureresponse relationships of veterinary pharmaceuticals. SIGNIFICANCE STATEMENTThis review delivers a much-needed summary of published information that provides insights into how disease and inflammation can influence the appropriateness of extrapolating laboratorybased dose-exposure-response relationships to what will occur in the actual veterinary patient. As part of this review, we also examine some of the method-associated issues to be considered when assessing the reported nature and magnitude of these changes.

Alternation of Organ-Specific Exposure in LPS-Induced Pneumonia Mice after the Inhalation of Tetrandrine Is Governed by Metabolizing Enzyme Suppression and Lysosomal Trapping

“…Thus, the observed overall agreement between the in vitro and in vivo metabolic clearances in response to inflammation reflected the contribution of the hepatic metabolizing enzyme. A significant amount of evidence has been reported on the relationships between inflammation on drug-metabolizing enzyme activity [ 13 , 21 , 35 ]. However, discrepancies still exist in available investigations.…”

“…However, discrepancies still exist in available investigations. Martinez et al [ 21 ] suggested that some of the apparent dissimilarities may be attributed to animal species and the duration of exposure to these cytokines.…”

“…Although a number of investigations into the characteristics of disease-PK and inhalation PK have been described in recent years [ 13 , 19 , 20 , 21 , 22 , 23 ], to the best of our knowledge to date, there are no acquired systemic PK and biodistribution profiles of an inhaled drug against respiratory viral infections under an acute pneumonia state. An evaluation of such kind would provide the required confidence in clinical transformation for inhalation drugs.…”

Assessing Mouse Kidney Parvovirus’ Ability to Confound Research by Examining its Effects on Renally Excreted Chemotherapeutics and its Impact on Pathologic Endpoints in the Adenine Model of Chronic Kidney Disease

“…Potential mechanisms for a decrease in volume of distribution, which would result in decreased clearance in the MKPV-infected B6 group, would include dehydration or increased drug protein binding. Both of these conditions may occur in disease, but in particular the latter may occur in a pro-inflammatory state associated with systemic infection 37 . MKPV-infected NSG mice had lower C0 than uninfected mice, suggesting a higher volume of distribution.…”

Comparison of Canine and Human Physiological Factors: Understanding Interspecies Differences that Impact Drug Pharmacokinetics

“…One of the challenges is the proportionally small amount of information on canine enzymes and transporters as compared to that in humans. Furthermore, a major drawback is the frequent reliance on mRNA for identification of location and changes in transporters and drug-metabolizing enzymes (159). It is difficult to compare human and canine enzyme and transporter activity on the basis of anything other than expressed activities.…”