Factors That Influence Microdialysis Recovery. Comparison of Experimental and Theoretical Microdialysis Recoveries in Rat Liver

• Published in: Journal of pharmaceutical sciences Vol. 86; no. 8; pp. 958 - 966
• Main Authors: Stenken, Julie A., Lunte, Craig E., Southard, Marylee Z., Ståhle, Lars
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.08.1997; John Wiley & Sons, Inc; Wiley; American Pharmaceutical Association
• Subjects: Analysis; Animals; Antipyrine - pharmacokinetics; Biological and medical sciences; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP1A2 Inhibitors; General pharmacology; Liver - enzymology; Liver - metabolism; Medical sciences; Medicin och hälsovetenskap; Microdialysis; Models, Biological; Pharmacology. Drug treatments; Phenacetin - pharmacokinetics; Rats; Rats, Sprague-Dawley; Biological fluid; Rat; Liver; Variations; Recovery; Separation method; Tissue; Enzymatic activity; Diffusion; Unspecific monooxygenase; Enzyme; Digestive system; Cytochrome P450; Sample; Interaction; Rodentia; Metabolism; Forecasting; Extracellular fluid; Vertebrata; Mammalia; Microdialysis; Animal; Limiting factor; Drug-metabolizing enzyme; Models; Oxidoreductases
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1021/js960269+

Inhibition of metabolic processes was used to assess the possible change in the recovery of material from a microdialysis probe implanted in vivo in rat liver. Phenacetin and antipyrine were perfused through a microdialysis probe implanted in the liver. Inhibition of phenacetin and antipyrine metabolism was achieved through an iv bolus dose of the cytochrome P450 suicide substrate 1-aminobenzotriazole (1- ABT). 1-ABT inhibited phenacetin clearance by 90%, thus also inhibiting metabolism by 90%. There was no statistical difference in the recovery of phenacetin and antipyrine across the microdialysis membrane in the liver between the control and metabolically inhibited animals. Partial differential equations were developed that describe the transport of analyte from the microdialysis probe and solved by an implicit finite-difference method to aid in the understanding of the above-mentioned microdialysis experiments. Predictions of microdialysis recovery obtained from the numerical model are compared with those found experimentally. The model could predict trends in the data, but not the actual experimental values. This suggests that predictions from this microdialysis model are essentially heuristic and as presently formulated can be used only to show mechanisms that affect recovery, but they cannot be used to accurately predict recovery. Prediction of actual recovery requires knowledge of the values of the parameters that describe chemical properties such as the in vivo diffusion coefficient, metabolism rate constant, and capillary exchange rate constant. For microdialysis experiments performed in the liver, capillary exchange and the rate of liver blood flow appear to be the dominant processes that facilitate net transport from a microdialysis probe rather than metabolic processes. These results indicate that microdialysis recoveries measured after inhibition of a concentration-dependent kinetic process via pharmacological challenge will change only when the kinetic process that is being challenged is large compared to the contribution of all concentration- dependent kinetic processes, including other metabolism routes, capillary exchange, or uptake that remove the analyte from the tissue space. It is concluded that the microdialysis recovery of a substance from the liver is not generally affected by liver metabolism.