Prediction of In Vivo Tissue Distribution from In Vitro Data 1. Experiments with Markers of Aqueous Spaces

AbstractPurpose. The aim of this study was to evaluate the ability of anin vitro method of tissue distribution to accurately predict total water andextracellular aqueous spaces using marker compounds urea and inulin. Methods. Slices (50–200 mg) of all the major tissues in the rat wereincubated with Hanks/HEPES pH7.4 buffer containing 14C-urea and3H-inulin for 2 h at 37°C. Tissue weight was noted before and afterincubation and the tissue-to-buffer ratios determined. Results.14C-Urea Kp estimates were generally greater than total tissuewater due to tissue swelling, which varied widely among the tissues,up to 41% in muscle. In most cases, Kp values were much closer toin vivo values after correcting for the 14C-urea in the imbibed media(Kpcorr). The method was able to distinguish between 14C-urea and3H-inulin Kp values and indicated that inulin occupied a smaller spacethan urea, which for the majority of tissues corresponded to theextracellular space. Conclusions. The Kpcorr values for14C-urea and Kp for 3H-inulin wereconsistent with total tissue water and extracellular space for the majorityof tissues studied, indicating their suitability as marker compounds forchecking the viability of this in vitro method for estimating tissuedistribution.

[1]  J. Allen.  Extracellular space in the central nervous system. , 1955, A.M.A. archives of neurology and psychiatry.

[2]  Kannan Krishnan,et al.  Molecular Structure-Based Prediction of the Partition Coefficients of Organic Chemicals for Physiological Pharmacokinetic Models , 1996 .

[3]  John E. Murphy,et al.  An in vitro method for determination of tissue partition coefficients of non‐volatile chemicals such as 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin and estradiol , 1995, Journal of applied toxicology : JAT.

[4]  T Iwatsubo,et al.  PREDICTION OF IN VIVO DRUG DISPOSITION FROM IN VITRO DATA BASED ON PHYSIOLOGICAL PHARMACOKINETICS , 1996, Biopharmaceutics & drug disposition.

[5]  J B Houston,et al.  Pharmacokinetics in Early Drug Research , 1997, Alternatives to laboratory animals : ATLA.

[6]  W. Sperry,et al.  Absorption of Water by Liver Slices from “Physiological” Saline Solutions , 1939 .

[7]  M. Rowland,et al.  Discrepancies in pharmacokinetic parameter estimation between bolus and infusion studies in the perfused rat hindlimb , 1995, Journal of Pharmacokinetics and Biopharmaceutics.

[8]  W. J. Campbell,et al.  The sodium and other ions of mammalian cerebral tissues, maintained and electrically stimulated in vitro. , 1962, The Biochemical journal.

[9]  H. Mcilwain,et al.  FLUID CONTENT AND COMPARTMENTS IN ISOLATED CEREBRAL TISSUES , 1961, Journal of neurochemistry.

[10]  H. Krebs,et al.  Accumulation of glutamic acid in isolated brain tissue. , 1949, The Biochemical journal.

[11]  S. Khor,et al.  Potential error in the measurement of tissue to blood distribution coefficients in physiological pharmacokinetic modeling. Residual tissue blood. I. Theoretical considerations. , 1991, Drug metabolism and disposition: the biological fate of chemicals.

[12]  S. R. Cohen.  The dependence of water content and “extracellular” marker spaces of incubated mouse brain slices on thickness , 1974, Experimental Brain Research.

[13]  R. S. Bourke.  Studies of the development and subsequent reduction of swelling of mammalian cerebral cortex under isosmotic conditions in vitro , 2004, Experimental Brain Research.

[14]  K. F. Rothe.  Fractional extracellular space and fractional water content of various rat tissues at different extracellular pH values and in uremia , 1979, Laboratory animals.

[15]  D. B. Tower,et al.  FLUID COMPARTMENTATION AND ELECTROLYTES OF CAT CEREBRAL CORTEX IN VITRO–I SWELLING AND SOLUTE DISTRIBUTION IN MATURE CEREBRAL CORTEX * , 1966, Journal of neurochemistry.

[16]  Vera Fiserova-Bergerova,et al.  Determination and prediction of tissue-gas partition coefficients , 1986, International archives of occupational and environmental health.

[17]  Melvin E. Andersen,et al.  Physiologically based pharmacokinetic and pharmacodynamic model for the inhibition of acetylcholinesterase by diisopropyfluorophosphate , 1990 .

[18]  M E Andersen,et al.  Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. , 1989, Toxicology and applied pharmacology.

[19]  K. Elliott,et al.  Water distribution in incubated slices of brain and other tissues. , 1956, Canadian journal of biochemistry and physiology.

[20]  M Rowland,et al.  Physiologic pharmacokinetic models and interanimal species scaling. , 1985, Pharmacology & therapeutics.

[21]  W. Runciman,et al.  The in vitro uptake and metabolism of lignocaine, procainamide and pethidine by tissues of the hindquarters of sheep. , 1991, Xenobiotica; the fate of foreign compounds in biological systems.

[22]  F. Theil,et al.  A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery. , 2000, Journal of pharmaceutical sciences.