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Anatomical-Physiological Approaches in Pharmacokinetics and Pharmacodynamics

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Abstract

Use of an anatomical-physiological approach allows an investigator an alternative to regarding the whole body as a ‘black box’ producing biofluid specimens for drug assay, and then blindly applying a formula-driven mathematical approach to determine the pharmacokinetics and pharmacodynamics of the drug of interest. Instead, it means the investigator can consider that the body is the sum of interacting parts or regions connected anatomically by blood flow carrying the drug of interest, that the regions as well as the carrier blood are not homogeneous because each has a physiological role, and that the parts or regions are connected neurally and humorally so that the response in any region or part of the system may be modified by and/or modulate effects at another region or part. Such an approach is difficult to institute experimentally because a complicated (and often expensive) preparation is usually required in animal studies, and is rarely possible in research with humans because of ethical constraints.

Despite these restrictions, there are many examples of the use of an anatomical-physiological approach allowing greater insight into pharmacological problems than would have been possible with a conventional ‘whole body’ approach alone. This paper takes a number of examples from the discipline of anaesthesia and pain management and groups them to illustrate the principles of the approach regarding drug arteriovenous equality and tissue distribution, multiple sites of clearance and multiple sites of action.

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Notes

  1. Distribution is more commonly used in pharmacokinetic literature and is used in this paper as the general term for the loss of drug from the circulating blood other than by elimination. Tissue uptake is the general term for referring to the drug gained by distribution into the tissues where the emphasis is placed on the consequences of drug being in the tissues. Redistribution is commonly used to denote loss from tissue back to blood, with or without ongoing distribution to other tissues.

  2. Elimination is the irreversible removal of the drug from the body by all processes of excretion and metabolism.

  3. Mean total body clearance is ‘mean’ because it is time-averaged, and is ‘total body’ because it is the sum of all regional clearances.

  4. A ‘compartment’ is a virtual volume that is homogeneous in the distribution of its analyte-solute and may or may not correspond to tissues and regions defined anatomically and physiologically.

  5. A region is defined as the tissue(s) between an afferent blood inflow and an efferent blood outflow; it may be heterogeneous or homogeneous with respect to tissue types or composition.

  6. To be more precise, concentrations of drug in blood sampled from short arteries (e.g. coronary and bronchial) or proximally from long arteries would also differ temporally from those blood sampled distally from long arteries (e.g. femoral or brachial)with respect to rapidly changing solute concentration, but the differences would be negligible compared with any relevant arterio-venous pair.

  7. Instantaneous rate of solute exchange (positive or negative, mass per unit time) between blood and tissue; equal to the (regional) clearance × arterial drug concentration.

  8. Strictly, afferent-efferent to allow for gradients such as pulmonary arterial-to-arterial and portal venous-to-hepatic venous; usually arterio-venous, for which the drug extraction ratio is given by the concentration difference/afferent concentration.

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Acknowledgements

The author acknowledges grant support from the National Health and Medical Research Council of Australia and from Ciroscience R&D Ltd, as well as the collaborative work with many colleagues, that went into providing the examples from the author’s personal collection of successful and unsuccessful experiments shown in this paper.

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Authors and Affiliations

  1. Centre for Anaesthesia and Pain Management Research, University of Sydney at Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia

    Laurence E. Mather (Professor of Anaesthesia and Analgesia (Research)

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Mather, L.E. Anatomical-Physiological Approaches in Pharmacokinetics and Pharmacodynamics. Clin Pharmacokinet 40, 707–722 (2001). https://doi.org/10.2165/00003088-200140100-00002

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