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Application of Microdialysis in Pharmacokinetic Studies

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Abstract

The objective of this review is to survey the recent literature regarding the various applications of microdialysis in pharmacokinetics. Microdialysis is a relatively new technique for sampling tissue extracellular fluid that is gaining popularity in pharmacokinetic and pharmacodynamic studies, both in experimental animals and humans. The first part of this review discusses various aspects of the technique with regard to its use in pharmacokinetic studies, such as: quantitation of the microdialysis probe relative recovery, interfacing the sampling technique with analytical instrumentation, and consideration of repeated procedures using the microdialysis probe. The remainder of the review is devoted to a survey of the recent literature concerning pharmacokinetic studies that apply the microdialysis sampling technique. While the majority of the pharmacokinetic studies that have utilized microdialysis have been done in the central nervous system, a growing number of applications are being found in a variety of peripheral tissue types, e.g. skin, muscle, adipose, eye, lung, liver, and blood, and these are considered as well. Given the rising interest in this technique, and the ongoing attempts to adapt it to pharmacokinetic studies, it is clear that microdialysis sampling will have an important place in studying drug disposition and metabolism.

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REFERENCES

  1. J. K. Hsiao, B. A. Ball, P. F. Morrison, I. N. Mefford, and P. M. Bungay. Effects of different semipermeable membranes on in vitro and in vivo performance of microdialysis probes. J. Neurochem. 54:1449–1452 (1990).

    Google Scholar 

  2. L. Stahle. Microdialysis in pharmacokinetics. Eur. J. Drug Metab Pharmacok. 18:89–96 (1993).

    Google Scholar 

  3. L. Stahle. Pharmacokinetic estimations from microdialysis data. Eur. J. Clin. Pharmacol. 43:289–294 (1992).

    Google Scholar 

  4. L. Stahle. Zero and first moment area estimation from microdialysis data. Eur. J. Clin. Pharmacol. 45:477–481 (1993).

    Google Scholar 

  5. P. N. Patsalos, W. T. Abed, M. S. Alavijeh, and M. T. O'Connell. The use of microdialysis for the study of drug kinetics: some methodological considerations illustrated with antipyrine in rat frontal cortex. Brit. J. Pharmacol. 115:503–509 (1995).

    Google Scholar 

  6. L. Stahle, S. Segersvard, and U. Ungerstedt. Theophylline concentration in the extracellular space of the rat brain: measurement by microdialysis and relation to behaviour. Eur. J. Pharmacol. 185:187–193 (1990).

    Google Scholar 

  7. P. F. Morrison, P. M. Bungay, J. K. Hsiao, B. A. Ball, I. N. Mefford, and R. L. Dedrick. Quantitative microdialysis: analysis of transients and application to pharmacokinetics in brain. J. Neurochem. 57:103–119 (1991).

    Google Scholar 

  8. S. L. Wong, Y. Wang, and R. J. Sawchuk. Analysis of zidovudine distribution to specific regions in rabbit brain using microdialysis. Pharm. Res. 9:332–338 (1992).

    Google Scholar 

  9. J. Henriksson, H. Rosdahl, T. Fuchi, Y. Oshida, and U. Ungerstedt. The use of microdialysis for the in vivo study of skeletal muscle glucose metabolism. In: G. Marechal and U. Carraro (Eds.), Muscle and Motility, Vol. 2, Intersept Ltd., Andover, UK (1990).

    Google Scholar 

  10. Y. Deguchi, T. Terasaki, S. Kawasaki, and A. Tsuji. Muscle microdialysis as a model study to relate the drug concentration in tissue interstitial fluid and dialysate. J. Pharmacobio-Dyn. 14:483–492 (1991).

    Google Scholar 

  11. D. Deleu, S. Sarre, G. Ebinger, and Y. Michotte. In vivo pharmacokinetics of levodopa and 3-O-methyldopa in muscle. A microdialysis study. Naunyn-Schmied. Arch Pharmacol. 344:514–519 (1991).

    Google Scholar 

  12. D. O. Scott, L. R. Sorenson, K. L. Steele, D. L. Puckett, and C. E. Lunte. In vivo microdialysis sampling for pharmacokinetic investigations. Pharm. Res. 8:389–392 (1991).

    Google Scholar 

  13. R. A. Yokel, D. D. Allen, D. E. Burgio, and P. J. McNamara. Antipyrine as a dialyzable reference to correct differences in efficiency among and within sampling devices during in vivo microdialysis. J. Pharmacol. Toxicol. Meth. 27:135–142 (1992).

    Google Scholar 

  14. P. M. Mertes, B. Beck, Y. Jaboin, A. Stricker, J. P. Carteaux, G. Pinelli, K. Elabassi, J. P. Villemot, C. Burlet, and M. Boulange. Microdialysis in the estimation of interstitial myocardial neuropeptide-Y release. Regulatory Peptides 49:81–90 (1993).

    Google Scholar 

  15. P. Lonnroth, P. A. Jansson, and U. Smith. A microdialysis method allowing characterization of intercellular water space in humans. Am. J. Physiol. 253:E228–E231 (1987).

    Google Scholar 

  16. P. A. Jansson, U. Smith, and P. Lonnroth. Interstitial glycerol concentration measured by microdialysis in two subcutaneous regions in humans. Am. J. Physiol. 258:E918–E922 (1990).

    Google Scholar 

  17. A. M. Herrera, D. O. Scott, and C. E. Lunte. Microdialysis sampling for determination of plasma protein binding of drugs. Pharm. Res. 7:1077–1081 (1990).

    Google Scholar 

  18. W. F. Elmquist and H. Yang. In vitro microdialysis study of the thermodynamics of cyclosporin A binding to components of human plasma. Curr. Sep. 12:54 (1993).

    Google Scholar 

  19. C. Nicholson and J. M. Phillips. Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum. J. Physiol. (Lond.) 321:225–257 (1981).

    Google Scholar 

  20. G. Amberg and N. Lindefors. Intracerebral microdialysis. II. Mathematical studies of diffusion kinetics. J. Pharmacol. Meth. 22:157–183 (1989).

    Google Scholar 

  21. N. Lindefors, G. Amberg, and U. Ungerstedt. Intracerebral microdialysis. I. Experimental studies of diffusion kinetics. J. Pharmacol. Meth. 22:141–156 (1989).

    Google Scholar 

  22. H. Benveniste and P. C. Huttemeier. Microdialysis: theory and application. Prog. Neurobiol. 35:195–215 (1990).

    Google Scholar 

  23. P. M. Bungay, P. F. Morrison, and R. L. Dedrick. Steady-state theory for quantitative microdialysis of solutes and water in vivo and in vitro. Life Sci. 46:105–119 (1990).

    Google Scholar 

  24. L. Stahle. The use of microdialysis in pharmacokinetics and pharmacodynamics. In: T. E. Robinson and J. B. Justice, Jr. (Eds.), Microdialysis in the Neurosciences, Techniques in the Behavioral and Neural Sciences, Vol. 7, Elsevier, Amsterdam, pp. 155–174 (1991).

    Google Scholar 

  25. P. F. Morrison, P. M. Bungay, J. K. Hsiao, I. N. Mefford, K. H. Dykstra, and R. L. Dedrick. Quantitative microdialysis. In: T. E. Robinson and J. B. Justice, Jr. (Eds.), Microdialysis in the Neurosciences, Techniques in the Behavioral and Neural Sciences, Vol. 7, Elsevier, Amsterdam, pp. 47–80 (1991).

    Google Scholar 

  26. K. H. Dykstra, J. K. Hsiao, P. E. Morrison, P. M. Bungay, I. N. Mefford, M. M. Scully, and R. L. Dedrick. Quantitative examination of tissue concentration profiles associated with microdialysis. J. Neurochem. 58:931–940 (1992).

    Google Scholar 

  27. K. H. Dykstra, A. Arya, D. A. Arriola, P. M. Bungay, P. F. Morrison, and R. L. Dedrick. Microdialysis study of zidovudine (AZT) transport in rat brain. J. Pharmacol. Exp. Ther. 267:1227–1235 (1993).

    Google Scholar 

  28. J. Kehr. A survey on quantitative microdialysis: theoretical models and practical implications. J. Neurosci. Meth. 48:251–261 (1993).

    Google Scholar 

  29. T. E. Robinson and J. B. Justice, Jr. (Eds.), Microdialysis in the Neurosciences, Techniques in the Behavioral and Neural Sciences, Vol. 7, Elsevier, Amsterdam (1991).

    Google Scholar 

  30. Y. Wang, S. L. Wong, and R. J. Sawchuk. Microdialysis calibration using retrodialysis and zero-net flux: application to a study of the distribution of zidovudine to rabbit cerebrospinal fluid and thalamus. Pharm. Res. 10:1411–1419 (1993).

    Google Scholar 

  31. I. Jacobson, M. Sandberg, and A. Hamberger. Mass transfer in brain dialysis devices: a new method for estimation of extracellular amino acids concentration. J. Neurosci. Meth. 15:263–268 (1985).

    Google Scholar 

  32. L. Stahle, S. Segersvard, and U. Ungerstedt. A comparison between three methods for estimation of extracellular concentrations of exogenous and endogenous compounds by microdialysis. J. Pharmacol. Meth. 25:41–52 (1990).

    Google Scholar 

  33. H. Benveniste. Brain microdialysis. J. Neurochem. 52:1667–179 (1989).

    Google Scholar 

  34. Y. Wang, S. L. Wong, and R. J. Sawchuk. Comparison of in vitro and in vivo calibration of microdialysis probes using retrodialysis. Curr. Sep. 10:87 (1991).

    Google Scholar 

  35. S. A. Wages, W. H. Church, and J. B. Justice. Sampling considerations for on-line microbore liquid chromatography of brain dialysate. Anal. Chem. 58:1649–1656 (1986).

    Google Scholar 

  36. P. T. Kissinger and R. E. Shoup. Optimization of LC apparatus for determinations in neurochemistry with an emphasis on microdialysis samples. J. Neurosci. Meth. 34:3–10 (1990).

    Google Scholar 

  37. R. M. Caprioli and S. N. Lin. On-line analysis of penicillin blood levels in the live rat by combined microdialysis/fast-atom bombardment mass spectroscopy. Proc. Natl. Acad. Sci. 87:240–243 (1990).

    Google Scholar 

  38. S. Y. Zhou, H. Zuo, J. F. Stobaugh, C. E. Lunte, and S. M. Lunte. Continuous in vivo monitoring of amino acid neurotransmitters by microdialysis sampling with on-line derivatization and capillary electrophoresis separation. Anal. Chem. 67:584–599 (1995).

    Google Scholar 

  39. M. A. Miller and R. S. Geary. RIA-linked microdialysis sampling in the awake rat: application to free-drug pharmacokinetics of hydrocortisone. J. Pharm. Biomed. Anal. 9:901–910 (1991).

    Google Scholar 

  40. K. M. Steele and C. E. Lunte. Microdialysis sampling coupled to on-line microbore liquid chromatography for pharmacokinetic studies. J. Pharm. Biomed. Anal. 13:149–154 (1995).

    Google Scholar 

  41. A. Chen and C. E. Lunte. Microdialysis sampling coupled on-line to fast microbore liquid chromatography. J. Chromatogr. A 691:29–35 (1995).

    Google Scholar 

  42. C. A. Marsden, I. A. Macdonald, M. H. Joseph, and D. Perrett. Electrochemical detection, HPLC and in vivo monitoring in the biosciences. J. Neurosci. Meth. 34:1–2 (1990).

    Google Scholar 

  43. V. F. Ruban. Determination of dopamine and its metabolites in microdialysates by capillary liquid chromatography with electrochemical detection. J. Chromatog. 619:11–115 (1993).

    Google Scholar 

  44. F. C. Cheng and J. S. Kuo. High-performance liquid chromatographic analysis with electrochemical detection of biogenic amines using microbore columns. J. Chromatog. B 665:1–13 (1995).

    Google Scholar 

  45. P. Gamache, E. Ryan, C. Svendsen, K. Murayama, and I. N. Acworth. Simultaneous measurement of monoamines, metabolites and amino acids in brain tissue and microdialysis perfusates. J. Chromatog. 614:213–220 (1993).

    Google Scholar 

  46. M. E. Hadwiger, M. Telting-Diaz, and C. E. Lunte. Liquid chromatographic determination of tacrine and its metabolities in rat bile microdialysates. J. Chromatog. B 655:235–241 (1994).

    Google Scholar 

  47. B. K. Malhotra, M. Lemaire, and R. J. Sawchuk. Investigation of the distribution of EAB 515 to cortical ECF and CSF in freely moving rats utilizing microdialysis. Pharm. Res. 11:1223–1232 (1994).

    Google Scholar 

  48. S. L. Wong, K. van Belle, and R. J. Sawchuk. Distributional transport kinetics of zidovudine between plasma and brain extracellular fluid/cerebrospinal fluid in the rabbit: Investigation of the inhibitory effect of probenecid utilizing microdialysis. J. Pharmacol. Exp. Ther. 264:899–909 (1993).

    Google Scholar 

  49. D. O. Scott, L. R. Sorensen, and C. E. Lunte. In vivo microdialysis sampling coupled to liquid chromatography for the study of acetaminophen metabolism. J. Chromatog. 506:461–469 (1990).

    Google Scholar 

  50. S. Tellez, N. Forges, A. roussin, and L. Hernandez. Coupling microdialysis with capillary electrophoresis: a new approach to the study of drug transfer between two compartments of the body in freely moving rats. J. Chromatog. 581:257–266 (1992).

    Google Scholar 

  51. B. L. Hogan, S. M. Lunte, J. F. Stobaugh, and C. E. Lunte. On-line coupling of in vivo microdialysis sampling with capillary electrophoresis. Anal. Chem. 66:596–602 (1994).

    Google Scholar 

  52. S. D. Menacherry and J. B. Justice. In vivo microdialysis and thermospray tandem mass spectroscopy of the dopamine uptake blocker 1[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)-piper azine (GBR-12909). Anal. Chem. 62:597–601 (1990).

    Google Scholar 

  53. P. Michelsen and G. Petterssen. An automated liquid chromatography/mass spectrometry system coupled on-line with microdialysis for the in vivo analysis of contrast agents. Rapid Commun. Mass Spectrom. 8:517–520 (1994).

    Google Scholar 

  54. L. J. Deterding, K. Dix, L. T. Burka, and K. B. Tomer. On-line coupling of in vivo microdialysis with tandem mass spectrometry. Anal. Chem. 64:2636–2641 (1992).

    Google Scholar 

  55. K. Dix, L. J. Deterding, L. T. Burka, and K. B. Tomer. Tris(2-chloroethyl) phosphate pharmacokinetics in the fischer 344 rat: a comparison of conventional methods and in vivo microdialysis coupled with tandem mass spectrometry. J. Pharm. Sci. 83:1622–1629 (1994).

    Google Scholar 

  56. Y. Takada, M. Yoshida, M. Sakairi, and H. Koizumi. Detection of gamma-aminobutyric acid in a living rat brain using in vivo microdialysis-capillary electrophoresis/mass spectrometry. Rapid Commun. Mass Spectrom. 9:895–896 (1995).

    Google Scholar 

  57. T. E. Robinson and D. M. Camp. The feasibility of repeated microdialysis for within-subjects design experiment: studies on the mesostriatal dopamine system. in Microdialysis in the Neurosciences, T. E. Robinson and J. B. Justice, Jr. (eds) Elsevier, 1991.

  58. Y. Wang and R. J. Sawchuk. Zidovudine transport in the rabbit brain during intravenous and intracerebroventricular infusion. J. Pharm. Sci. 84:871–876 (1995).

    Google Scholar 

  59. Q. Wang, H. Yang, D. W. Miller, and W. F. Elmquist. Effect of the P-glycoprotein inhibitor, cyclosporin A, on the distribution of rhodamine-123 to the brain: An in vivo microdialysis study in freely-moving rats. Biochem. Biophys. Res. Commun. 211:719–726 (1995).

    Google Scholar 

  60. E. C. M. de Lange, M. Danhof, A. G. de Boer, and D. D. Breimer. Critical factors of intracerebral microdialysis as a technique to determine the pharmacokinetics of drugs in rat brain. Brain Res. 666:1–8 (1994).

    Google Scholar 

  61. J. Georgieva, J. Luthman, B. Mohringe, and O. Magnusson. Tissue and microdialysate changes after repeated and permanent probe implantation in the striatum of freely moving rats. Brain Res. Bull. 31:463–470 (1993).

    Google Scholar 

  62. H. Benveniste and N. H. Diemer. Cellular reactions to implantation of a microdialysis tube in the rat hippocampus. Acta Neuropathol. 74:234–238 (1987).

    Google Scholar 

  63. J. A. Yergey and M. P. Heyes. Brain eicosanoid formation following acute penetration injury as studied by in vivo microdialysis. J. Cereb. Blood Flow Metab. 10:143–146 (1990).

    Google Scholar 

  64. H. Benveniste, J. Drejer, A. Schousboe, and N. H. Diemer. Regional cerebral glucose phosphorylation and blood flow after insertion of a microdialysis fiber through the dorsal hippocampus in the rat. J. Neurochem. 49:729–734 (1987).

    Google Scholar 

  65. D. M. Camp and T. E. Robinson. On the use of multiple probe insertions at the same site for repeated intracerebral microdialysis experiments in the nigrostriatal dopamine system of rats. J. Neurochem. 58:1706–1715 (1992).

    Google Scholar 

  66. D. D. Allen, P. A. Crooks, and R. A. Yokel. 4-trimethylammonium antipyrine: A quaternary ammonium nonradionuclide marker for blood-brain barrier integrity during in vivo microdialysis. J. Pharmacol. Tox. Methods. 28:129–135 (1992).

    Google Scholar 

  67. U. Tossman and U. Ungerstedt. Microdialysis in the study of extracellular levels of amino acids in the rat brain. Acta Physiol. Scand. 128:9–14 (1986).

    Google Scholar 

  68. T. A. Aasmundstad, J. Morland, and R. E. Paulsen. Distribution of morphine 6-glucuronide and morphine across the blood-brain barrier in awake, freely moving rats investigated by in vivo microdialysis sampling. J. Pharmacol. Exper. Ther. 275:435–441 (1995).

    Google Scholar 

  69. T. Terasaki, Y. Deguchi, Y. Kasama, W. M. Pardridge, and A. Tsuji. Determination of in vivo steady-state unbound drug concentration in the brain interstitial fluid by microdialysis. Int. J. Pharmaceut. 81:143–152 (1992).

    Google Scholar 

  70. V. A. Levin, H. D. Landahl, and M. A. Freeman-Dove. The application of brain capillary permeability coefficient measurements to pathological conditions and the selection of agents which cross the blood-brain barrier. J. Pharmacokinet. Biopharm. 4:499–519 (1976).

    Google Scholar 

  71. M. Fontaine, Q. Wang, H. Yang, and W. F. Elmquist. Effect of interleukin-2 on the blood brain barrier: An in vivo microdialysis study. Pharm. Res. 12:S–406 (1995).

    Google Scholar 

  72. I. Westergren, B. Nystrom, A. Hamberger, and B. B. Johansson. Interacerebral dialysis and the blood-brain barrier. J. Neurochem. 64:229–234 (1995).

    Google Scholar 

  73. O. Major, T. Shdanova, L. Duffek, and Z. Nagy. Continuous monitoring of blood-brain barrier opening to Cr51-EDTA by microdialysis following probe injury. Acta Neurochirurgica. Suppl. 51:46–48 (1990).

    Google Scholar 

  74. M. E. Morgan, D. Singhal, and B. D. Anderson. Quantitative assessment of blood-brain barrier damage during microdialysis. J. Pharmacol. Exper. Ther. 277:1167–1176 (1996).

    Google Scholar 

  75. L. H. Parsons and J. B. Justice. Quantitative approaches to in vivo brain microdialysis. Crit. Reviews in Neurobiology 8:189–220 (1994).

    Google Scholar 

  76. T. Terasaki Y. Deguchi H. Sato, K. Hirai, and A. Tsuji. In vivo transport of a dynorphin-like analgesic peptide, E-2078, through the blood-brain barrier: An application of brain microdialysis. Pharm. Res. 8:815–820 (1991).

    Google Scholar 

  77. C. Sauernheimer, K. M. Williams, K. Brune, and G. Geisslinger. Application of microdialysis to the pharmacokinetics of analgesics: problems with reduction of dialysis efficiency in vivo. J. Pharmacol. Toxicol. Methods 32:149–154 (1994).

    Google Scholar 

  78. M. Ekblom, M. Gardmark, and M. Hammarlund-Udenaes. Estimation of unbound concentrations of morphine from microdialysate concentrations by use of nonlinear regression analysis in vivo and in vitro during steady state conditions. Life Sciences 51:449–460 (1992).

    Google Scholar 

  79. F. F. Matos, H. Rollema, and A. I. Basbaum. Simultaneous measurement of extracellular morphine and serotonin in brain tissue and CSF by microdialysis in awake rats. J. Neurochem. 58:1773–1781 (1992).

    Google Scholar 

  80. M. J. Barjavel J-M. Scherrmann, and H. N. Bargava. Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study. Brit. J. Pharmacol. 116:3205–3210 (1995).

    Google Scholar 

  81. F. Stain, M. J. Barjavel, P. Sandouk, M. Plotkine, J-M. Scherrmann, and H. N. Bhargava. Analgesic response and plasma and brain extracellular fluid pharmacokinetics of morphine and morphine-6-,β-D-glucuronide in the rat. J. Pharmacol. Exper. Ther. 274:852–857 (1995).

    Google Scholar 

  82. T. Mindermann, H. Ladolt, W. Zimmerli, Z. Rajacic, and O. Gratzl. Penetration of rifampicin into brain tissue and cerebral extracellular space of rats. J. Antimicrob. Chemother 31:731–737 (1993).

    Google Scholar 

  83. L. Granero, M. Santiago, J. Cano, A. Machado, and J-E. Peris. Analysis of ceftriaxone and ceftazidime distribution in cerebrospinal fluid of and cerebral extracellular space in awake rats by in vivo microdialysis. Antimicrob. Agents Chemother. 39:2728–2731 (1995).

    Google Scholar 

  84. H. Yang, Q. Wang, and W. F. Elmquist. Fluconazole distribution to the brain: A crossover study in freely-moving rats using in vivo microdialysis. Pharm. Res. 13:1570–1575 (1996).

    Google Scholar 

  85. M. A. Hedaya and R. J. Sawchuk. Effect of probenecid on the renal and nonrenal clearances of zidovudine and its distribution to the cerebrospinal fluid of the rabbit. J. Pharm. Sci. 78:716–722 (1989).

    Google Scholar 

  86. Y. Wang and R. J. Sawchuk. Zidovudine transport in the rabbit brain during intravenous and intracerebroventricular infusion. J. Pharm. Sci. 84:871–876 (1995).

    Google Scholar 

  87. E. Ljungdahl-Stahle, E. Guzenda, D. Bottiger, B. Wahren, B. Oberg, and L. Stahle. Penetration of zidovudine and 3′fluoro-3′-deoxythymidine into the brain, muscle tissue, and veins in Cynomolgus monkeys: relation to antiviral action. Antimicrob. Agents Chemother. 36:2418–2422 (1992).

    Google Scholar 

  88. L. Stahle, and B. Oberg. Pharmacokinetics and distribution over the blood-brain barrier of two acyclic guanosine analogs in rats, studied by microdialysis. Antimicrob. Agents Chemother. 36:339–342 (1992).

    Google Scholar 

  89. E. C. M. de Lange, J. D. de Vries, C. Zurcher, M. Danhof, A. G. de Boer, and D. D. Breimer. The use of intracerebral microdialysis for the determination of pharmacokinetic profiles of anticancer drugs in tumor-bearing rat brain. Pharm. Res. 12:1924–1931 (1995).

    Google Scholar 

  90. D. Devineni, A. Klein-Szanto, and J. M. Gallo. In vivo microdialysis to characterize drug transport in brain tumors: analysis of methotrexate uptake in rat glioma-2 (RG-2) bearing rats, in press, Cancer Chemother. Pharmacol.

  91. D. Devineni, A. Klein-Szanto, and J. M. Gallo. Uptake of temozolomide in a rat glioma model in the presence and absence of the angiogenesis inhibitor TNP-470. Cancer Res. 56:1983–1987 (1996).

    Google Scholar 

  92. A. Sakata, I. Tamai, K. Kawazu, Y. Deguchi, T. Ohnishi, A. Saheki, and A. Tsuji. In vivo evidence for ATP-dependent and P-glycoprotein mediated transport of cyclosporin A at the blood-brain barrier. Biochem. Pharmacol. 48:1989–1992 (1994).

    Google Scholar 

  93. D. E. Burgio, M. P. Gosland, and P. J. McNamara. Modulation effects of cyclosporine on etoposide pharmacokinetics and CNS distribution in the rat utilizing microdialysis. Biochem. Pharmacol. 51:987–992 (1996).

    Google Scholar 

  94. R. D. Scheyer, M. J. During, D. D. Spencer, J. A. Cramer, and R. H. Mattson. Measurement of carbamazepine and carbamazepine epoxide in the human brain using in vivo microdialysis. Neurology 44:1469–1472 (1994).

    Google Scholar 

  95. R. D. Scheyer, M. J. During, J. M. Hochholzer, D. D. Spencer, J. A. Cramer, and R. H. Mattson. Phenytoin concentrations in the human brain: an in vivo microdialysis study. Epilepsy Res. 18:227–232 (1994).

    Google Scholar 

  96. L. Stahle, C. Alm, B. Ekquist, B. Lundquist, and T. Tomson. Monitoring free extracellular valproic acid by microdialysis in epileptic patients. Thera. Drug Monit. 18:14–18 (1996).

    Google Scholar 

  97. J. H. Wolf, L. Veenma-Van der Duin, and J. Korf. The extracellular concentration of the anti-epileptic drug valproate in the rat brain as determined with microdialysis and an automated HPLC procedure. J. Pharm. Pharmacol. 43:101–106 (1991).

    Google Scholar 

  98. P. L. Golden, K. R. Brouwer, and G. M. Pollack. Assessment of valproic acid serum-cerebrospinal fluid transport by microdialysis. Pharm. Res. 10:1765–1771 (1993).

    Google Scholar 

  99. D. F. Welty, G. P. Schielke, M. G. Vartanian, and C. P. Taylor. Gabapentin anticonvulsant action in rats: disequilibrium with peak drug concentrations in plasma and brain microdialysate. Epilepsy Res. 16:175–181 (1993).

    Google Scholar 

  100. Y. Wang and D. F. Welty. The simultaneous estimation of the influx and efflux blood-brain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach. Pharm. Res. 13:398–403 (1996).

    Google Scholar 

  101. Y. Deguchi, K. Inabe, K. Tomiyasu, K. Nozawa, S. Yamada, and R. Kimura. Study on brain interstitial fluid distribution and blood-brain barrier transport of baclofen in rats by microdialysis. Pharm. Res. 12:1838–1844 (1995).

    Google Scholar 

  102. R. Takahashi, M. Hagiwara, M. Watabe, R. Kan, and Y. Takahashi. Carbamazepine and carbamazepine-10, 11-epoxide concentrations in rat brain and blood evaluated by in vivo microdialysis. Jap. J. Psych. Neuro. 47:293–294 (1993).

    Google Scholar 

  103. K. Van Belle, S. Sarre, G. Ebinger, and Y. Michotte. Brain, liver, and blood distribution kinetics of carbamazepine and its metabolic interaction with clomipramine in rats: a quantitative microdialysis study. J. Pharmacol. Exper. Ther. 272:1217–1222 (1995).

    Google Scholar 

  104. K. Van Belle, T. Dzeka, S. Sarre, G. Ebinger, and Y. Michotte. In vitro and in vivo microdialysis calibration for the measurement of carbamazepine and its metabolites in rat brain tissue using the internal reference technique. J. Neurosci. Methods 49:167–173 (1993).

    Google Scholar 

  105. N. Kurata, M. Inagaki, M. Iwase, Y. Nishimura, Y. Kiuchi, Y. Yamazaki, S. Kobayashi K Oguchi, E. Uchida, and H. Yasuhara. Pharmacokinetic study of trimethadione and its metabolite in blood, liver and brain by microdialysis in conscious, unrestrained rats. Res Commun. Mol. Path. Pharmacol. 89:45–56 (1995).

    Google Scholar 

  106. L. Stahle. Drug distribution studies with microdialysis: I. Tissue dependent difference in recovery between caffeine and theophylline. Life Sciences 49:1835–1842 (1991).

    Google Scholar 

  107. L. Stahle, S. Segersvard, and U. Ungerstedt. Drug distribution studies with microdialysis II. Caffeine and theophylline in blood, brain and other tissues in rats. Life Sciences 49:1843–1852 (1991).

    Google Scholar 

  108. T. Nakazono, T. Murakami, S. Sakai, Y. Higashi, and N. Yata. Application of microdialysis for study of caffeine distribution into brain and cerebrospinal fluid in rats. Chem. Pharm. Bull. 40:2510–2515 (1992).

    Google Scholar 

  109. R. A. Yokel, V. Lidums, P. J. McNamara, and U. Ungerstedt. Aluminum distribution into brain and liver of rats and rabbits following intravenous aluminum lactate or citrate: a microdialysis study. Toxicol. Appl. Pharmacol. 107:153–163 (1991).

    Google Scholar 

  110. R. A. Yokel, V. Lidums, and U. Ungerstedt. Aluminum mobilization by desferrioxamine assessed by microdialysis of the blood, liver and brain. Toxicology 66:313–324 (1991).

    Google Scholar 

  111. D. D. Allen, C. Orvig, and R. A. Yokel. Evidence for energy-dependent transport of aluminum out of brain extracellular fluid. Toxicology 98:31–39 (1995).

    Google Scholar 

  112. M. Telting-Diaz and C. E. Lunte. Distribution of tacrine across the blood-brain barrier in awake, freely moving rats using in vivo microdialysis sampling. Pharm. Res. 10:44–48 (1993).

    Google Scholar 

  113. R. C. Brundage. Investigation of the brain distribution and presystemic metabolism of tacrine and selected metabolites using microdialysis of brain and blood. Ph.D. dissertation, University of Minnesota (1996).

  114. U. Warpman, X. Zhang, and A. Nordberg. Effect of tacrine on in vivo release of dopamine and its metabohtes in the striatum of freely moving rats. J. Pharmacol. Exper. Ther. 277:917–922 (1996).

    Google Scholar 

  115. M. J. Alonso, A. Bruelisauer, P. Misslin, and M. Lemaire. Microdialysis sampling to determine the pharmacokinetics of unbound SDZ-ICM 567 in blood and brain in awake, freely-moving rats. Pharm. Res. 12:291–294 (1995).

    Google Scholar 

  116. Y. Sato, S. Shibanoki, M. Sugahara, and K. Ishikawa. Measurement and pharmacokinetic analysis of imipramine and its metabolite by brain microdialysis. Br. J. Pharmacol. 112:625–629 (1994).

    Google Scholar 

  117. B. K. Malhotra, M. Lemaire, J. F. Brouillard, and R. J. Sawchuk. High-performance liquid chromatographic analysis of (s)-a-amino-5-phosphonomethly[1,1′-biphenyl]-3-propanoic acid (EAB 515) in brain and blood microdialysate (on-line) and in plasma ultrafiltrate of freely moving rats. J. Chromatog. B. 679:167–176 (1996).

    Google Scholar 

  118. B. K. Malhotra, R. C. Brundage, M. Lemaire, and R. J. Sawchuk. Modeling the route of administration-based enhancement in the brain delivery of EAB 515, studied by microdialysis. J. Drug Targeting in press (1997).

  119. E. C. M. de Lange, M. B. Hesselink, M. Danhof, A. G. de Boer, and D. D. Breimer. The use of intracerebral microdialysis to determine changes in blood-brain barrier transport characteristics. Pharm. Res. 12:129–133 (1995).

    Google Scholar 

  120. E. C. M. de Lange, M. R. Bouw, J. W. Mandema, M. Danhof, A. G. de Boer, and D. D. Breimer. Application of intracerebral microdialysis to study regional distribution kinetics of drugs in the rat brain. Brit. J. Pharmacol. 116:2538–2544 (1995).

    Google Scholar 

  121. P. Arner and J. Bolinder. Microdialysis of adipose tissue. J. Int. Med. 230:381–386 (1991).

    Google Scholar 

  122. P. A. Jansson, T. Veneman, N. Nurjhan, and J. Gerich. An improved method to calculate adipose tissue interstitial substrate recovery for microdialysis studies. Life Sci. 54:1621–1624 (1994).

    Google Scholar 

  123. M. C. Linhares and P. T. Kissinger. Pharmacokinetic monitoring in subcutaneous tissue using in vivo capillary ultrafiltration probes. Pharm. Res. 10:598–602 (1993).

    Google Scholar 

  124. M. C. Linhares and P. T. Kissinger. Pharmacokinetic studies using microdialysis probes in subcutaneous tissue: effects of the co-administration of ethanol and acetaminophen. J Pharm. Biomed. Anal. 12:619–627 (1994).

    Google Scholar 

  125. K. Matsuyama, M. Nakashima, Y. Nakaboh, M. Ichikawa, T. Yano, and S. Satoh. Application of in vivo microdialysis to transdermal absorption of methotrexate in rats. Pharm. Res. 11:684–686 (1994).

    Google Scholar 

  126. K. Matsuyama, M. Nakashima, M. Ichikawa, T. Yano, S. Satoh, and S. Goto. In vivo microdialysis for the transdermal absorption of valproate in rats. Biological & Pharmaceutical Bulletin 17:1395–1398 (1994).

    Google Scholar 

  127. J. M. Ault, C. E. Lunte, N. M. Meltzer, and C. M. Riley. Microdialysis sampling for the investigation of dermal drug transport. Pharm. Res. 9:1256–1261 (1992).

    Google Scholar 

  128. J. M. Ault, C. M. Riley, N. M. Meltzer, and C. E. Lunte. Dermal microdialysis sampling in vivo. Pharm. Res. 11:1631–1639 (1994).

    Google Scholar 

  129. M. C. Linhares and P. T. Kissinger. In vivo sampling using loop microdialysis probes coupled to a liquid chromatograph. J. Chromatog. 578:157–163 (1992).

    Google Scholar 

  130. D. Deleu. S. Sarre, Y. Michotte, and G. Ebinger. Simultaneous in vivo microdialysis in plasma and skeletal muscle: a study of the pharmacokinetic properties of levodopa by noncompartmental analysis. J. Pharm. Sci. 83:25–28, (1994).

    Google Scholar 

  131. D. Deleu. S. Sarre. G. Ebinger, and Y. Michotte. The effect of carbidopa and entacapone pretreatment on the L-dopa pharmacokinetics and metabolism in blood plasma and skeletal muscle in beagle dog: an in vivo microdialysis study. J. Pharmacol. Exp. Therap. 273:1323–1331, (1995).

    Google Scholar 

  132. J. Ben-Nun, R. L. Cooper, S. J. Cringle, and I. J. Constable. A new technique for in vivo pharmacokinetic measurements. Arch. Ophthamol. 106:254–259 (1988).

    Google Scholar 

  133. J. Ben-Nun, D. A. Joyce, R. L. Cooper, S. J. Cringle, and I. J. Constable. Pharmacokinetics of intravitreal injection. Assessment of a gentamicin model by ocular dialysis. Invest. Ophthamol. Vis. Sci. 30:1055–1061 (1989).

    Google Scholar 

  134. J. Waga, A. Ohta, and B. Ehinger. Intraocular microdialysis with permanently implanted probes in rabbit. Acta Ophthalmologica. 69:618–624 (1991).

    Google Scholar 

  135. N. Stempels, M. J. Tassignon, and S. Sarre. A removable ocular microdialysis system for measuring vitreous biogenic amines. Graefes Archive for Clinical & Experimental Ophthalmology. 231:651–655 (1993).

    Google Scholar 

  136. N. Stempels, M. J. Tassignon, S. Sarre, and J. Nguyen-Legros. Microdialysis measurement of catecholamines in rabbit vitreous after retinal laser photocoagulation. Experimental Eye Research. 59:433–439, (1994).

    Google Scholar 

  137. J. Waga and B. Ehinger. Passage of drugs through different intraocular microdialysis membranes. Graefes Archive for Clinical & Experimental Ophthalmology 233:31–37 (1995).

    Google Scholar 

  138. P. M. Hughes, R. Krishnamoorthy, and A. K. Mitra. Vitreous disposition of two acycloguanosine antivirals in the albino and pigmented rabbit models: a novel ocular microdialysis technique. J. Ocular Pharmacol. Therap. 12:209–224 (1996).

    Google Scholar 

  139. A. I. Kuzmin, O. V. Tskitishvili, L. I. Serebryakova, V. I. Kapelko, I. V. Majorova, and O. S. Medvedev. Allopurinol: kinetics, inhibition of xanthine oxidase activity, and protective effect in ischemic-reperfused canine heart as studied by cardiac microdialysis. Journal of Cardiovascular Pharmacology 25:564–571 (1995).

    Google Scholar 

  140. P. Lonnroth, J. Carlsten, L. Johnson, and U. Smith. Measurements by microdialysis of free tissue concentrations of propranolol. J. Chromatog. 568:419–425 (1991).

    Google Scholar 

  141. E. J. Eisenberg, P. Conzentino, W. M. Eickhoff, and K. C. Cundy. Pharmacokinetic measurement of drugs in lung epithelial lining fluid by microdialysis: aminoglycoside antibiotics in rat bronchi. J. Pharmacol Toxicolog. Methods 29:93–98 (1993).

    Google Scholar 

  142. D. O. Scott, Lunte C. E. In vivo microdialysis sampling in the bile, blood, and liver of rats to study the disposition of phenol. Pharm. Res. 10:335–42, 1993.

    Google Scholar 

  143. O. Ekstrom. A. Andersen, D. J. Warren. K. E. Giercksky, and L. Slordal. Evaluation of methotrexate tissue exposure by in situ microdialysis in a rat model. Cancer Chemotherapy & Pharmacology 34:297–301 (1994).

    Google Scholar 

  144. Z. Chen and R. W. Steger. Plasma microdialysis: A technique for continuous plasma sampling in freely moving rats. J. Pharmacol. Toxicol. Meth. 29:111–118 (1993).

    Google Scholar 

  145. P. A. Evrard, G. Deridder, and R. K. Verbeeck. Intravenous microdialysis in the mouse and the rat: Development and pharmacokinetic application of a new probe. Pharm. Res. 13:12–17 (1996).

    Google Scholar 

  146. Kurata N. Inagaki M. Kobayashi S. Nishimura Y. Oguchi K., and Yasuhara H. Antipyrine concentrations in liver and blood monitored by microdialysis of unrestrained conscious rats. Res. Commun. Chem. Path. & Pharmacol. 79:363–369 (1993).

    Google Scholar 

  147. D. O. Scott, L. R. Sorensen, and C. E. Lunte. In vivo microdialysis sampling coupled to liquid chromatography for the study of acetaminophen metabolism. J. Chromatog. 506:461–469 (1990).

    Google Scholar 

  148. Scott D. O., Bell M. A., and Lunte C. E. Microdialysis-perfusion sampling for the investigation of phenol metabolism. J. Pharmaceut. Biomed. Anal. 7:1249–1259 (1989).

    Google Scholar 

  149. M. Ekblom, M. Hammarlund-Udenaes, T. Lundqvist, and P. Sjoberg. Potential use of microdialysis in pharmacokinetics: A protein binding study. Pharm. Res. 9:155–158 (1992).

    Google Scholar 

  150. S. Sarre, K. Van Belle, I. Smolders, G. Krieken, and Y. Michotte. The use of microdialysis for the determination of plasma protein binding of drugs. J. Pharm. Biomed. Anal. 10:735–739 (1992).

    Google Scholar 

  151. A. L. Quellec, S. Dupin, A. E. Tufenkj, P. Genissel, and G. Houin. Microdialysis: An alternative for in vitro and in vivo protein binding studies. Pharm. Res. 11:835–838 (1994).

    Google Scholar 

  152. H. Yang and W. F. Elmquist. The binding of cyclosporin A to human plasma: An in vitro microdialysis study. Pharm. Res. 13:620–625 (1996).

    Google Scholar 

  153. Q. Wang, and W. F. Elmquist. Amphotericin B plasma protein-binding studies using in vitro microdialysis and on-line HPLC. Pharm. Res. 10:S-394 (1994).

    Google Scholar 

  154. M. Nakashima, N. Takeuchi, M. Hamada, K. Matsuyama, M. Ichikawa, and S. Goto. In vivo microdialysis for pharmacokinetic investigations: a plasma protein binding study of valproate in rabbits. Biol. Pharm. Bull. 17:1630–1634 (1994).

    Google Scholar 

  155. P. A. Evrard, J. Cumps, and R. K. Verbeeck. Concentration-dependent plasma protein binding of flubiprofen in the rat: An in vivo microdialysis study. Pharm. Res. 13:18–22 (1996).

    Google Scholar 

  156. R. K. Dubey, C. V. McAllister, M. Inoue, and G. R. Wilkinson. Plasma binding and transport of diazepam across the blood-brain barrier. J. Clin. Invest. 84:1155–1159 (1989).

    Google Scholar 

  157. M. Telting-Diaz, D. O. Scott, and C. E. Lunte. Intravenous microdialysis sampling in awake, freely-moving rats. Anal. Chem. 64:806–810 (1992).

    Google Scholar 

  158. M. Ehrnebo. Drug binding to blood cells. In M. M. Reidenberg and S. Erill (eds.), Drug-protein binding, Praeger Pub., New York, 1986, pp. 128–137.

    Google Scholar 

  159. H. Lorentzen, F. Kallehave, H. J. Kolmos, U. Knigge, J. Bulow, and F. Gottrup. Gentamicin concentrations in human subcutaneous tissue. Antimicrob. Agents Chemotherap. 40:1785–1789 (1996).

    Google Scholar 

  160. M. Muller, O. Haag, A. Georgopoulos, W. Weinger, B. Jansen, G. Stanek, H. Pehamberger, E. Agneter, and H. G. Eichler. Characterization of peripheral-compartment kinetics of antibiotics by in vivo microdialysis in humans. Antimicrob. Agents Chemotherap. 40:2703–2709 (1996).

    Google Scholar 

  161. B. Blochl-Daum, M. Muller, V. Meisinger, H. G. Eichler, A. Fassolt, and H. Pehamberger. Measurement of extracellular fluid carboplatin kinetics in melanoma metastases with microdialysis. Brit. J. Cancer 73:920–924 (1996).

    Google Scholar 

  162. M. Muller, R. Schnid, O. Wagner, B. V. Osten, H. Shaganfar, and H. G. Eichler. In vivo characterization of transdermal transport by microdialysis. J. Control. Release 37:49–57 (1995).

    Google Scholar 

  163. M. Muller, R. Schmid, M. Nieszpaur-Los, A. Fassolt, P. Lonnroth, P. Fasching, and H. G. Eichler. Key metabolite kinetics in human skeletal muscle during ischaemia and reperfusion: measurement by microdialysis. Eur. J. Clin. Invest. 25:601–607 (1995).

    Google Scholar 

  164. E. Hagstrom, P. Arner, P. Engfeldt, S. Rossner, and J. Bolinder. In vivo subcutaneous glucose kinetics after glucose ingestion in obesity and fasting. Scand. J. Clin. Lab. Invest. 50:129–136 (1990).

    Google Scholar 

  165. L. Simonsen, J. Bulow, and J. Madsen. Adipose tissue metabolism in humans determined by vein catheterization and microdialysis techniques. Am. J. Physiol. 266:E357–65 (1994).

    Google Scholar 

  166. G. Fellander, J. Nordenstrom, U. Ungerstedt, P. Arner, and J. Bolinder. Influence of operation on glucose metabolism and lipolysis in human adipose tissue: a microdialysis study. Eur. J. Surg. 160:87–95 (1994).

    Google Scholar 

  167. P. Arner and J. Bulow. Assessment of adipose tissue metabolism in man: comparison of Fick and microdialysis techniques. Clin. Science 85:247–56 (1993).

    Google Scholar 

  168. P. A. Jansson, J. P. Fowelin, H. P. von Schenck, U. P. Smith, and P. N. Lonnroth. Measurement by microdialysis of the insulin concentration in subcutaneous interstitial fluid. Importance of the endothelial barrier for insulin. Diabetes 42:1469–73 (1993).

    Google Scholar 

  169. L. Stahle, P. Arner, and U. Ungerstedt. Drug distribution studies with microdialysis. III: Extracellular concentration of caffeine in adipose tissue in man. Life Sci. 49:1853–8 (1991).

    Google Scholar 

  170. M. Muller, R. Schmid, A. Georgopoulos, A. Buxbaum, C. Wasicek, and H. G. Eichler. Application of microdialysis to clinical pharmacokinetics in humans. Clin. Pharmacol. Ther. 57:371–380 (1995).

    Google Scholar 

  171. M. Muller, B. V. Osten, R. Schmid, E. Piegler, I. Gerngross, H. Buchegger, and H. G. Eichler. Theophylline kinetics in peripheral tissues in vivo in humans. Naunyn-Schmied. Arch Pharmacol. 352:438–441 (1995).

    Google Scholar 

  172. K. M. Hargreaves and A. Costello. Glucocorticoids suppress levels of immunoreactive bradykinin in inflamed tissue as evaluated by microdialysis probes. Clin. Pharmacol. Ther. 48:168–178: (1990).

    Google Scholar 

  173. G. S. Metry, P. O. Attman, P. Lonnroth, S. N. Beshara, and M. Aurell. Urea kinetics during hemodialysis measured by microdialysis—a novel technique. Kidney International 44:622–629 (1993).

    Google Scholar 

  174. L. Hegemann, C. Forstinger, B. Partsch, I. Lagler, S. Krotz, and K. Wolff. Microdialysis in cutaneous pharmacology: kinetic analysis of transdermally delivered nicotine. J. Invest. Derm. 104:839–843 (1995).

    Google Scholar 

  175. C. Anderson, T. Andersson, and M. Molander. Ethanol absorption across human skin measured by in vivo microdialysis technique. Acta Dermato-Venereologica 71:389–393 (1991).

    Google Scholar 

  176. C. Anderson, T. Andersson, and K. Wardell. Changes in skin circulation after insertion of a microdialysis probe visualized by laser Doppler perfusion imaging. J. Invest. Derm. 102:807–811 (1994).

    Google Scholar 

  177. J. de Boer, H. Plijter-Groendijk, and J. Korf. Microdialysis probe for transcutaneous monitoring of ethanol and glucose in humans. J. Appl. Physiol. 75:2825–2830 (1993).

    Google Scholar 

  178. H. Stjernstrom, T. Karlsson, U. Ungerstedt, and L. Hillered. Chemical monitoring of intensive care patients using intravenous microdialysis. Intensive Care Med. 19:423–428 (1993).

    Google Scholar 

  179. R. Kanthan, A. Shuaib, R. Griebel, and H Miyashita. Intracerebral microdialysis. In vivo study of an acute focal ischemic model of the human brain. Stroke 26:870–873 (1995).

    Google Scholar 

  180. M. J. During. In vivo neurochemistry of the conscious human brain: intrahippocampal microdialysis in epilepsy. In: T. E. Robinson and J. B. Justice, Jr. (Eds.), Microdialysis in the Neurosciences. Techniques in the Behavioral and Neural Sciences, Vol. 7, Elsevier, Amsterdam, pp. 425–442 (1991).

    Google Scholar 

  181. L. H. Parsons, A. D. Smith, and J. B. Justice, Jr. The in vivo microdialysis recovery of dopamine is altered independently of basal level by 6-hydroxydopamine lesions to the nucleus accumbens. J. Neurosci. Methods 40:139–147 (1991).

    Google Scholar 

  182. S. Menacherry, W. Hubert, and J. B. Justice Jr. In vivo calibration of microdialysis probes for exogenous compounds. Anal. Chem. 64:577–583 (1992).

    Google Scholar 

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Elmquist, W.F., Sawchuk, R.J. Application of Microdialysis in Pharmacokinetic Studies. Pharm Res 14, 267–288 (1997). https://doi.org/10.1023/A:1012081501464

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