Insight into tissue unbound concentration: Utility in drug discovery and development

Current Drug Metabolism

Volumn 14, Issue 3, 2013, Pages 324-340

  Mariappan, T Thanga ^a   Mandlekar, Sandhya ^b   Marathe, Punit ^b  

^a SYNGENE INTERNATIONAL LTD   (India)

^b BRISTOL MYERS SQUIBB   (United States)

Author keywords

Pharmacodynamics; Pharmacokinetics; Protein binding; Tissue distribution; Tissue unbound drug concentration

Indexed keywords

AMITRIPTYLINE; APOMORPHINE; DOXORUBICIN; IMIPRAMINE; LAPATINIB; MORPHINE; MULTIDRUG RESISTANCE PROTEIN; N (4 BETA GLUCURONYL 3 NITROBENZYLOXYCARBONYL)DOXORUBICIN; OROSOMUCOID; THIORIDAZINE;

ALLERGIC ENCEPHALOMYELITIS; BLOOD BRAIN BARRIER; BRAIN METASTASIS; BRAIN SLICE; CARDIOTOXICITY; CEREBROSPINAL FLUID; DRUG CEREBROSPINAL FLUID LEVEL; DRUG EFFICACY; DRUG TISSUE LEVEL; ENANTIOMER; HEART VENTRICLE ARRHYTHMIA; HUMAN; INTERSTITIAL FLUID; KIDNEY SLICE; MICRODIALYSIS; NONHUMAN; PERMEABILITY; POSITRON EMISSION TOMOGRAPHY; PROSTATE HYPERTROPHY; RECEPTOR OCCUPANCY; REVIEW; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; STEREOCHEMISTRY; TISSUE DISTRIBUTION; TISSUE HOMOGENATE; TISSUE PERFUSION;

ANIMALS; DRUG DISCOVERY; HUMANS; PHARMACEUTICAL PREPARATIONS; PHARMACOKINETICS; TISSUE DISTRIBUTION;

EID: 84877997299     PISSN: 13892002     EISSN: 18755453     Source Type: Journal    
DOI: 10.2174/1389200211314030008     Document Type: Review

References (108)

1. 1] Fessey, R. E.; Austin, R. P.; Barton, P.; Davis, A. M.; Wenlock, M. C., The role of plasma protein binding in drug discovery. In Pharmacokinetic profiling in drug research, Wiley-VCH Verlag GmbH & Co. KGaA: 2007; pp 119-141.
2. Trainor, G. L. The importance of plasma protein binding in drug discovery. Expert Opin. Drug Discov., 2007, 2, 51-64. (Pubitemid 47078697)
3. Bergström, C.; Charman, S.; Nicolazzo, J. Computational prediction of CNS drug exposure based on a novel in vivo dataset. Pharm. Res., 2012, 1-12.
4. H, P.; G.R, L. Medicinal chemical properties of successful central nervous system drugs. NeuroRx, 2005, 2, 541-553.
5. Doran, A.; Obach, R. S.; Smith, B. J.; Hosea, N. A.; Becker, S.; Callegari, E.; Chen, C.; Chen, X.; Choo, E.; Cianfrogna, J.; Cox, L. M.; Gibbs, J. P.; Gibbs, M. A.; Hatch, H.; Hop, C. E. C. A.; Kasman, I. N.; LaPerle, J.; Liu, J.; Liu, X.; Logman, M.; Maclin, D.; Nedza, F. M.; Nelson, F.; Olson, E.; Rahematpura, S.; Raunig, D.; Rogers, S.; Schmidt, K.; Spracklin, D. K.; Szewc, M.; Troutman, M.; Tseng, E.; Tu, M.; Van Deusen, J. W.; Venkatakrishnan, K.; Walens, G.; Wang, E. Q.; Wong, D.; Yasgar, A. S.; Zhang, C. The impact of p-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: Evaluation using the mdr1a/1b knockout mouse model. Drug Metab. Dispos., 2005, 33, 165-174. (Pubitemid 40023528)
6. Reichel, A. The role of blood-brain barrier studies in the pharmaceutical industry. Curr. Drug Metab., 2006, 7, 183-203.
7. Fridén, M.; Bergström, F.; Wan, H.; Rehngren, M.; Ahlin, G.; Hammarlund-Udenaes, M.; Bredberg, U. Measurement of unbound drug exposure in brain: Modeling of pH partitioning explains diverging results between the brain slice and brain homogenate methods. Drug Metab. Dispos., 2011, 39, 353-362.
8. Bundgaard, C.; Jensen, C. J. N.; Garmer, M. Species comparison of in vivo p-glycoprotein-mediated brain efflux using mdr1a-deficient rats and mice. Drug Metab. Dispos., 2012, 40, 461-466.
9. Poulin, P.; Kenny, J. R.; Hop, C. E. C. A.; Haddad, S. In vitro-in vivo extrapolation of clearance: Modeling hepatic metabolic clearance of highly bound drugs and comparative assessment with existing calculation methods. J. Pharm. Sci., 2012, 101, 838-851.
10. Reichel, A. Addressing central nervous system (CNS) penetration in drug discovery: Basics and implications of the evolving new concept. Chem. Biodivers., 2009, 6, 2030-2049.
11. Fridén, M.; Gupta, A.; Antonsson, M.; Bredberg, U.; Hammarlund-Udenaes, M. In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug Metab. Dispos., 2007, 35, 1711-1719. (Pubitemid 47296068)
12. Liu, X.; Chen, C.; Smith, B. J. Progress in brain penetration evaluation in drug discovery and development. J. Pharmacol. Exp. Ther., 2008, 325, 349-356. (Pubitemid 351574780)
13. Hammarlund-Udenaes, M.; Fridén, M.; Syvänen, S.; Gupta, A. On the rate and extent of drug delivery to the brain. Pharm. Res., 2008, 25, 1737-1750.
14. Fridén, M.; Ducrozet, F.; Middleton, B.; Antonsson, M.; Bredberg, U.; Hammarlund-Udenaes, M. Development of a high-throughput brain slice method for studying drug distribution in the central nervous system. Drug Metab. Dispos., 2009, 37, 1226-1233.
15. Vastag, M.; Keseru, G. Current in vitro and in silico models of blood-brain barrier penetration: A practical view. Curr. Opin. Drug Discov. Develop., 2009, 12, 115-124.
16. Cory Kalvass, J.; Maurer, T. S. Influence of nonspecific brain and plasma binding on CNS exposure: Implications for rational drug discovery. Biopharm. Drug Dispos., 2002, 23, 327-338. (Pubitemid 36124162)
17. Liu, X.; Van Natta, K.; Yeo, H.; Vilenski, O.; Weller, P. E.; Worboys, P. D.; Monshouwer, M. Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid. Drug Metab. Dispos., 2009, 37, 787-793.
18. Kalvass, J. C.; Olson, E. R.; Cassidy, M. P.; Selley, D. E.; Pollack, G. M. Pharmacokinetics and pharmacodynamics of seven opioids in p-glycoprotein-competent mice: Assessment of unbound brain ec50,u and correlation of in vitro, preclinical, and clinical data. J. Pharmacol. Exp. Ther., 2007, 323, 346-355. (Pubitemid 47443282)
19. Pfefferkorn, J. A.; Guzman-Perez, A.; Litchfield, J.; Aiello, R.; Treadway, J. L.; Pettersen, J.; Minich, M. L.; Filipski, K. J.; Jones, C. S.; Tu, M.; Aspnes, G.; Risley, H.; Bian, J.; Stevens, B. D.; Bourassa, P.; D'Aquila, T.; Baker, L.; Barucci, N.; Robertson, A. S.; Bourbonais, F.; Derksen, D. R.; MacDougall, M.; Cabrera, O.; Chen, J.; Lapworth, A. L.; Landro, J. A.; Zavadoski, W. J.; Atkinson, K.; Haddish-Berhane, N.; Tan, B.; Yao, L.; Kosa, R. E.; Varma, M. V.; Feng, B.; Duignan, D. B.; El-Kattan, A.; Murdande, S.; Liu, S.; Ammirati, M.; Knafels, J.; DaSilva-Jardine, P.; Sweet, L.; Liras, S.; Rolph, T. P. Discovery of (s)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1h-imidazol-1- yl)propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus. J. Med. Chem., 2011, 55, 1318-1333.
20. Pfefferkorn, J. A.; Litchfield, J.; Hutchings, R.; Cheng, X.-M.; Larsen, S. D.; Auerbach, B.; Bush, M. R.; Lee, C.; Erasga, N.; Bowles, D. M.; Boyles, D. C.; Lu, G.; Sekerke, C.; Askew, V.; Hanselman, J. C.; Dillon, L.; Lin, Z.; Robertson, A.; Olsen, K.; Boustany, C.; Atkinson, K.; Goosen, T. C.; Sahasrabudhe, V.; Chupka, J.; Duignan, D. B.; Feng, B.; Scialis, R.; Kimoto, E.; Bi, Y.-A.; Lai, Y.; El-Kattan, A.; Bakker-Arkema, R.; Barclay, P.; Kindt, E.; Le, V.; Mandema, J. W.; Milad, M.; Tait, B. D.; Kennedy, R.; Trivedi, B. K.; Kowala, M. Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: A bench-to-bedside case study on tissue selective drug distribution. Bioorg. Med. Chem. Lett., 2011, 21, 2725-2731.
21. Maurer, T. S.; DeBartolo, D. B.; Tess, D. A.; Scott, D. O. Relationship between exposure and nonspecific binding of thirtythree central nervous system drugs in mice. Drug Metab. Dispo., 2005, 33, 175-181. (Pubitemid 40023529)
22. Summerfield, S. G.; Lucas, A. J.; Porter, R. A.; Jeffrey, P.; Gunn, R. N.; Read, K. R.; Stevens, A. J.; Metcalf, A. C.; Osuna, M. C.; Kilford, P. J.; Passchier, J.; Ruffo, A. D. Toward an improved prediction of human in vivo brain penetration. Xenobiotica, 2008, 38, 1518-1535.
23. Steve Harris, J. D., Katie Critchell, Charlie Malloy, Christine Tyman, Mark Savage Assessment of the rapid equilibrium dialysis (RED) device for the determination of plasma protein binding (PPB). http://www.piercenet.com/files/ PfizerREDposterSep07.pdf (Accessed July 04, 2012).
24. Becker, S.; Liu, X. Evaluation of the utility of brain slice methods to study brain penetration. Drug Metab. Dispos., 2006, 34, 855-861.
25. Liu, X.; Smith, B. J.; Chen, C.; Callegari, E.; Becker, S. L.; Chen, X.; Cianfrogna, J.; Doran, A. C.; Doran, S. D.; Gibbs, J. P.; Hosea, N.; Liu, J.; Nelson, F. R.; Szewc, M. A.; Van Deusen, J. Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration. Drug Metab. Dispos., 2006, 34, 1443-1447. (Pubitemid 44285383)
26. Newman, G. C.; Hospod, F. E.; Wu, P. Thick brain slices model the ischemic penumbra. J. Cereb. Blood Flow Metab., 1988, 8, 586-597.
27. Khor, S. P.; Mayersohn, M. Potential error in the measurement of tissue to blood distribution coefficients in physiological pharmacokinetic modeling. Residual tissue blood. I. Theoretical considerations. Drug Metab. Dispos., 1991, 19, 478-485.
28. Friden, M.; Ljungqvist, H.; Middleton, B.; Bredberg, U.; Hammarlund-Udenaes, M. Improved measurement of drug exposure in the brain using drug-specific correction for residual blood. J. Cereb. Blood Flow Metab., 2010, 30, 150-161.
29. Watanabe, T.; Kusuhara, H.; Watanabe, T.; Debori, Y.; Maeda, K.; Kondo, T.; Nakayama, H.; Horita, S.; Ogilvie, B. W.; Parkinson, A.; Hu, Z.; Sugiyama, Y. Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drugdrug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments. Drug Metab. Dispos., 2011, 39, 1031-1038.
30. Daniel, W. A.; Wójcikowski, J. The role of lysosomes in the cellular distribution of thioridazine and potential drug interactions. Toxicol. Appl. Pharmacol., 1999, 158, 115-124. (Pubitemid 29343434)
31. Zhang, X.; Liu, L.; Zhang, X.; Ma, K.; Rao, Y.; Zhao, Q.; Li, F. Analytical methods for brain targeted delivery system in vivo: Perspectives on imaging modalities and microdialysis. J. Pharm. Biomed. Anal., 2012, 59, 1-12.
32. Joukhadar, C.; Müller, M. Microdialysis: Current applications in clinical pharmacokinetic studies and its potential role in the future. Clin. Pharmacokinet., 2005, 44, 895-913. (Pubitemid 41252841)
33. Sarter, M.; Bruno, J. P.; Parikh, V. Abnormal neurotransmitter release underlying behavioral and cognitive disorders: Toward concepts of dynamic and function-specific dysregulation. Neuropsychopharmacology, 2006, 32, 1452-1461. (Pubitemid 46920162)
34. Chaurasia, C.; Müller, M.; Bashaw, E.; Benfeldt, E.; Bolinder, J.; Bullock, R.; Bungay, P.; DeLange, E.; Derendorf, H.; Elmquist, W.; Hammarlund-Udenaes, M.; Joukhadar, C.; Kellogg, D. J.; Lunte, C.; Nordstrom, C.; Rollema, H.; Sawchuk, R.; Cheung, B.; Shah, V.; Stahle, L.; Ungerstedt, U.; Welty, D.; Yeo, H. Aaps-fda workshop white paper: Microdialysis principles, application, and regulatory perspectives report from the joint AAPS-FDA workshop, november 4-5, 2005, nashville, tn. AAPS J., 2007, 9, E48-E59.
35. Chefer, V. I.; Thompson, A. C.; Zapata, A.; Shippenberg, T. S., Overview of brain microdialysis. In Current protocols in neuroscience, John Wiley & Sons, Inc.: 2001.
36. Cremers, T. I. F. H.; De Vries, M. G.; Huinink, K. D.; Loon, J. P. v.; Hart, M. v. d.; Ebert, B.; Westerink, B. H. C.; De Lange, E. C. M. Quantitative microdialysis using modified ultraslow microdialysis: Direct rapid and reliable determination of free brain concentrations with the metaquant technique. J. Neurosci. Methods, 2009, 178, 249-254.
37. Groothuis, D. R.; Ward, S.; Schlageter, K. E.; C. Itskovich, A.; Schwerin, S. C.; Allen, C. V.; Dills, C.; M. Levy, R. Changes in blood-brain barrier permeability associated with insertion of brain cannulas and microdialysis probes. Brain Res., 1998, 803, 218-230. (Pubitemid 28392150)
38. De Lange, E. C. M.; Danhof, M.; De Boer, A. G.; Breimer, D. D. Critical factors of intracerebral microdialysis as a technique to determined the pharmacokinetics of drugs in rat brain. Brain Res., 1994, 666, 1-8. (Pubitemid 24359646)
39. Kovar, A.; Costa, T. D.; Derendorf, H. Comparison of plasma and free tissue levels of ceftriaxone in rats by microdialysis. J. Pharm. Sci., 1997, 86, 52-56. (Pubitemid 127489657)
40. Buerger, C.; Plock, N.; Dehghanyar, P.; Joukhadar, C.; Kloft, C. Pharmacokinetics of unbound linezolid in plasma and tissue interstitium of critically ill patients after multiple dosing using microdialysis. Antimicrob. Agents Chemother., 2006, 50, 2455-2463. (Pubitemid 43993186)
41. Zeitlinger, M. A.; Traunmüller, F.; Abrahim, A.; Müller, M. R.; Erdogan, Z.; Müller, M.; Joukhadar, C. A pilot study testing whether concentrations of levofloxacin in interstitial space fluid of soft tissues may serve as a surrogate for predicting its pharmacokinetics in lung. Int. J. Antimicrob. Agents, 2007, 29, 44-50. (Pubitemid 44959788)
42. Stolle, L.; Arpi, M.; Jørgensen, P.; Riegels-Nielsen, P.; Keller, J. In situ gentamicin concentrations in cortical bone an experimental study using microdialysis in bone. Acta Orthop., 2003, 74, 611-616. (Pubitemid 37310971)
43. Stolle, L. B.; Arpi, M.; Holmberg-Jørgensen, P.; Riegels-Nielsen, P.; Keller, J. Application of microdialysis to cancellous bone tissue for measurement of gentamicin levels. J. Antimicrob. Chemother., 2004, 54, 263-265. (Pubitemid 39029005)
44. Zamboni, W. C.; Strychor, S.; Joseph, E.; Walsh, D. R.; Zamboni, B. A.; Parise, R. A.; Tonda, M. E.; Yu, N. Y.; Engbers, C.; Eiseman, J. L. Plasma, tumor, and tissue disposition of stealth liposomal ckd-602 (S-CKD602) and nonliposomal CKD-602 in mice bearing a375 human melanoma xenografts. Clin. Cancer Res., 2007, 13, 7217-7223. (Pubitemid 350276909)
45. Shen, D. D.; Artru, A. A.; Adkison, K. K. Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics. Adv. Drug Deliv. Rev., 2004, 56, 1825-1857. (Pubitemid 39307054)
46. De Lange, E. C. M.; Danhof, M. Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: Implications of the barriers between blood and brain. Clin. Pharmacokinet., 2002, 41, 691-703. (Pubitemid 34948192)
47. Lin, J. H. CSF as a surrogate for assessing CNS exposure: An industrial perspective. Curr. Drug Metab., 2008, 9, 46-59. (Pubitemid 351201670)
48. Lin, J. H.; Lu, A. Y. H. Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol. Rev., 1997, 49, 403-449. (Pubitemid 28030947)
49. Nyberg, G.; Axelsson, R.; Martensson, E. Cerebrospinal fluid concentrations of thioridazine and its main metabolites in psychiatric patients. Eur. J. Clin. Pharmacol., 1981, 19, 139-148. (Pubitemid 11204242)
50. Wode-Helgodt, B.; Alfredsson, G. Concentrations of chlorpromazine and two of its active metabolites in plasma and cerebrospinal fluid of psychotic patients treated with fixed drug doses. Psychopharmacology (Berl). 1981, 73, 55-62. (Pubitemid 11105460)
51. Kodaira, H.; Kusuhara, H.; Fujita, T.; Ushiki, J.; Fuse, E.; Sugiyama, Y. Quantitative evaluation of the impact of active efflux by p-glycoprotein and breast cancer resistance protein at the bloodbrain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogate. J. Pharmacol. Exp. Ther., 2011, 339, 935-944.
52. Xiao, G.; Black, C.; Hetu, G.; Sands, E.; Wang, J.; Caputo, R.; Rohde, E.; Gan, L.-S. L. Cerebrospinal fluid can be used as a surrogate to assess brain exposures of breast cancer resistance protein and p-glycoprotein substrates. Drug Metab. Dispos., 2012, 40, 779-787.
53. Wan, H. I.; Soares, H.; Waring, J. F. Use of cerebrospinal fluid biomarkers in clinical trials for schizophrenia and depression. Biomark. Med., 2012, 6, 119-129.
54. Kielbasa, W.; Stratford, R. E. Exploratory translational modeling approach in drug development to predict human brain pharmacokinetics and pharmacologically relevant clinical doses. Drug Metab. Dispos., 2012, 40, 877-883.
55. Research, S. D. In-vivo brain microdialysis & neurochemistry invivo receptor occupancy assays. http://www.suven.com/Pdf/ Brain%20Microdialysis%20Neurochemistry%20and%20Receptor %20Occupancy%20- %20Assays%20and%20Validation.pdf (Accessed July 04, 2012).
56. Liu, X.; Vilenski, O.; Kwan, J.; Apparsundaram, S.; Weikert, R. Unbound brain concentration determines receptor occupancy: A correlation of drug concentration and brain serotonin and dopamine reuptake transporter occupancy for eighteen compounds in rats. Drug Metab. Dispos., 2009, 37, 1548-1556.
57. Bundgaard, C.; Sveigaard, C.; Brennum, L. T.; Stensbøl, T. B. Associating in vitro target binding and in vivo CNS occupancy of serotonin reuptake inhibitors in rats: The role of free drug concentrations. Xenobiotica, 2011, 42, 256-265.
58. Yata, N.; Toyoda, T.; Murakami, T.; Nishiura, A.; Higashi, Y. Phosphatidylserine as a determinant for the tissue distribution of weakly basic drugs in rats. Pharm. Res., 1990, 7, 1019-1025. (Pubitemid 20366728)
59. Terasaki, T.; Iga, T.; Sugiyama, Y.; Hanano, M. Interaction of doxorubicin with nuclei isolated from rat liver and kidney. J. Pharm. Sci., 1984, 73, 524-528. (Pubitemid 14134332)
60. Wierzba, K.; Sugiyama, Y.; Okudaira, K.; Iga, T.; Hanano, M. Tubulin as a major determinant of tissue distribution of vincristine. J. Pharm. Sci., 1987, 76, 872-875. (Pubitemid 18006833)
61. Gong, Y.; Zhao, Z.; McConn, D.; Beaudet, B.; Tallman, M.; Speake, J.; Ignar, D.; Krise, J. Lysosomes contribute to anomalous pharmacokinetic behavior of melanocortin-4 receptor agonists. Pharm. Res., 2007, 24, 1138-1144. (Pubitemid 46798893)
62. Macintyre, A. C.; Cutler, D. J. The potential role of lysosomes in tissue distribution of weak bases. Biopharm. Drug Dispos., 1988, 9, 513-526.
63. Daniel, W. A.; Wójcikowski, J. Lysosomal trapping as an important mechanism involved in the cellular distribution of perazine and in pharmacokinetic interaction with antidepressants. Eur. Neuropsychopharmacol., 1999, 9, 483-491. (Pubitemid 30089061)
64. Gupta, A.; Chatelain, P.; Massingham, R.; Jonsson, E. N.; Hammarlund-Udenaes, M. Brain distribution of cetirizine enantiomers: Comparison of three different tissue-to-plasma partition coefficients: Kp, Kp,u, and Kp,UU. Drug Metab. Dispos., 2006, 34, 318-323. (Pubitemid 43145034)
65. Takahashi, H.; Ogata, H.; Kanno, S.; Takeuchi, H. Plasma protein binding of propranolol enantiomers as a major determinant of their stereoselective tissue distribution in rats. J. Pharmacol. Exp. Ther., 1990, 252, 272-278. (Pubitemid 20067724)
66. Hanada, K.; Akimoto, S.; Mitsui, K.; Mihara, K.; Ogata, H. Enantioselective tissue distribution of the basic drugs disopyramide, flecainide and verapamil in rats: Role of plasma protein and tissue phosphatidylserine binding. Pharm. Res., 1998, 15, 1250-1256. (Pubitemid 28401717)
67. Sam, E.; Sarre, S.; Michotte, Y.; Verbeke, N. Distribution of apomorphine enantiomers in plasma, brain tissue and striatal extracellular fluid. Eur. J. Pharmacol., 1997, 329, 9-15. (Pubitemid 27264852)
68. Skhirtladze, K.; Hutschala, D.; Fleck, T.; Thalhammer, F.; Ehrlich, M.; Vukovich, T.; Muller, M.; Tschernko, E. M. Impaired target site penetration of vancomycin in diabetic patients following cardiac surgery. Antimicrob. Agents Chemother., 2006, 50, 1372-1375.
69. Korstanje, C.; Krauwinkel, W.; Van Doesum-Wolters, F. L. C. Tamsulosin shows a higher unbound drug fraction in human prostate than in plasma: A basis for uroselectivity? Br. J. Clin. Pharmacol., 2011, 72, 218-225.
70. Tunblad, K.; Ederoth, P.; Gärdenfors, A.; Hammarlund-Udenaes, M.; Nordström, C. H. Altered brain exposure of morphine in experimental meningitis studied with microdialysis. Acta Anaesthesiol. Scand., 2004, 48, 294-301. (Pubitemid 38295340)
71. Bartels, A. L. Blood-brain barrier p-glycoprotein function in neurodegenerative disease. Curr. Pharm. Des., 2011, 17, 2771-2777.
72. Cheng, Z.; Zhang, J.; Liu, H.; Li, Y.; Zhao, Y.; Yang, E. Central nervous system penetration for small molecule therapeutic agents does not increase in multiple sclerosis-and alzheimer's diseaserelated animal models despite reported blood-brain barrier disruption. Drug Metab. Dispos., 2010, 38, 1355-1361.
73. Mürdter, T. E.; Sperker, B.; Kivistö, K. T.; McClellan, M.; Fritz, P.; Friedel, G.; Linder, A.; Bosslet, K.; Toomes, H.; Dierkesmann, R.; Kroemer, H. K. Enhanced uptake of doxorubicin into bronchial carcinoma:-glucuronidase mediates release of doxorubicin from a glucuronide prodrug (HMR 1826) at the tumor site. Cancer Res., 1997, 57, 2440-2445. (Pubitemid 27255904)
74. Mürdter, T. E.; Friedel, G.; Backman, J. T.; McClellan, M.; Schick, M.; Gerken, M.; Bosslet, K.; Fritz, P.; Toomes, H.; Kroemer, H. K.; Sperker, B. Dose optimization of a doxorubicin prodrug (hmr 1826) in isolated perfused human lungs: Low tumor pH promotes prodrug activation by-glucuronidase. J. Pharmacol. Exp. Ther., 2002, 301, 223-228. (Pubitemid 34250298)
75. Taskar, K.; Rudraraju, V.; Mittapalli, R.; Samala, R.; Thorsheim, H.; Lockman, J.; Gril, B.; Hua, E.; Palmieri, D.; Polli, J.; Castellino, S.; Rubin, S.; Lockman, P.; Steeg, P.; Smith, Q. Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm. Res., 2012, 29, 770-781.
76. Lockman, P. R.; Mittapalli, R. K.; Taskar, K. S.; Rudraraju, V.; Gril, B.; Bohn, K. A.; Adkins, C. E.; Roberts, A.; Thorsheim, H. R.; Gaasch, J. A.; Huang, S.; Palmieri, D.; Steeg, P. S.; Smith, Q. R. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin. Cancer Res., 2010, 16, 5664-5678.
77. Mauric, O.; Thallinger, C.; Kugler, S. A.; Joukhadar, S. M.; Kovar, F. M.; Konz, K. H.; Graninger, W.; Joukhadar, C. The ability of fluconazole to penetrate into ventilated, healthy and inflamed lung tissue in a model of severe sepsis in rats. Pharmacology, 2011, 87, 130-134.
78. Yu, L. J.; Chen, Y.; Treadway, J. L.; McPherson, R. K.; McCoid, S. C.; Gibbs, E. M.; Hoover, D. J. Establishment of correlation between in vitro enzyme binding potency and in vivo pharmacological activity: Application to liver glycogen phosphorylase a inhibitors. J. Pharmacol. Exp. Ther., 2006, 317, 1230-1237. (Pubitemid 43764128)
79. Yarim, G. F.; Karahan, S. Regional brain and sex differences in the plasma progesterone concentration of sheep. Small Ruminant Research, 2007, 71, 98-102. (Pubitemid 46891193)
80. Sailasuta, N.; Ernst, T.; Chang, L. Gender, age and regional differences of brain glutamate concentration in healthy subjects. Proc. Intl. Soc. Mag. Reson. Med., 2006, 14, 486.
81. Glennon, R. A.; Dukat, M.; Westkaemper, R. B. Serotonin receptor subtypes and ligands http://www.acnp.org/g4/GN401000039/Ch039.html (Accessed July 09, 2012).
82. Westerhout, J.; Danhof, M.; De Lange, E. C. M. Preclinical prediction of human brain target site concentrations: Considerations in extrapolating to the clinical setting. J. Pharm. Sci., 2011, 100, 3577-3593.
83. Pfefferkorn, J. 'Muscle-sparing' statins: Preclinical profiles and future clinical use. Curr. Opin. Investig. Drugs, 2009, 10, 245-252.
84. Erion, M.; Bullough, D.; Lin, C.; Hong, Z. Hepdirect prodrugs for targeting nucleotide-based antiviral drugs to the liver. Curr. Opin. Investig. Drugs, 2006, 7, 109-117. (Pubitemid 43230906)
85. von Geldern, T. W.; Tu, N.; Kym, P.R.; Link, J. T.; Jae, H. S.; Lai, C.; Apelqvist, T.; Rhonnstad, P.; Hagberg, L.; Koehler, K.; Grynfarb, M.; Goos-Nilsson, A.; Sandberg, J.; Osterlund, M.; Barkhem, T.; Höglund, M.; Wang, J.; Fung, S.; Wilcox, D.; Nguyen, P.; Jakob, C.; Hutchins, C.; Färnegardh, M.; Kauppi, B.; Ohman, L.; Jacobson, P.B. Liver-selective glucocorticoid antagonists: A novel treatment for type 2 diabetes. J. Med. Chem., 2004, 47, 4213-4230. (Pubitemid 39056076)
86. Bebernitz, G.; Beaulieu, V.; Dale, B.; Deacon, R.; Duttaroy, A.; Gao, J.; Grondine, M.; Gupta, R.; Kakmak, M.; Kavana, M.; Kirman, L.; Liang, J.; Maniara, W.; Munshi, S.; Nadkarni, S.; Schuster, H.; Stams, T.; Denny, I. S.; Taslimi, P.; Vash, B.; Caplan, S. Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes. J. Med. Chem., 2009, 52, 6142-6152.
87. Koltun, D. O.; Zilbershtein, T. M.; Migulin, V. A.; Vasilevich, N. I.; Parkhill, E. Q.; Glushkov, A. I.; McGregor, M. J.; Brunn, S. A.; Chu, N.; Hao, J.; Mollova, N.; Leung, K.; Chisholm, J. W.; Zablocki, J. Potent, orally bioavailable, liver-selective stearoyl-coa desaturase (scd) inhibitors. Bioorg. Med. Chem. Lett., 2009, 19, 4070-4074.
88. Wang, Q.; Xu, C.; Behnia, K.; Marathe, P., Use of hepatocyte preparations in vitro to predict liver-to-plasma ratio in vivo. In DDI-2011, 14th International Conference of Drug-Drug Interactions, Seattle, WA, USA, 2011.
89. Ezzine, S.; Varin, F. Interstitial muscle concentrations of rocuronium under steady-state conditions in anaesthetized dogs: Actual versus predicted values. Br. J. Anaesth., 2005, 94, 49-56. (Pubitemid 40074907)
90. Morgan, P.; Van Der Graaf, P. H.; Arrowsmith, J.; Feltner, D. E.; Drummond, K. S.; Wegner, C. D.; Street, S. D. A. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving phase II survival. Drug Discov. Today, 2012, 17, 419-424.
91. Watson, J.; Wright, S.; Lucas, A.; Clarke, K. L.; Viggers, J.; Cheetham, S.; Jeffrey, P.; Porter, R.; Read, K. D. Receptor occupancy and brain free fraction. Drug Metab. Dispos., 2009, 37, 753-760.
92. Myrianthefs, P.; Markantonis, S. L.; Vlachos, K.; Anagnostaki, M.; Boutzouka, E.; Panidis, D.; Baltopoulos, G. Serum and cerebrospinal fluid concentrations of linezolid in neurosurgical patients. Antimicrob. Agents Chemother., 2006, 50, 3971-3976. (Pubitemid 44865137)
93. Liu, K. K. C.; Cornelius, P.; Patterson, T. A.; Zeng, Y.; Santucci, S.; Tomlinson, E.; Gibbons, C.; Maurer, T. S.; Marala, R.; Brown, J.; Kong, J. X.; Lee, E.; Werner, W.; Wenzel, Z.; Vage, C. Design and synthesis of orally-active and selective azaindane 5ht2c agonist for the treatment of obesity. Bioorg. Med. Chem. Lett., 2010, 20, 266-271.
94. Nakajima, M.; Yamada, T.; Kusuhara, T.; Furukawa, H.; Takahashi, M.; Yamauchi, A.; Kataoka, Y. Results of quinacrine administration to patients with creutzfeldt-jakob disease. Dement. Geriatr. Cogn. Disord., 2004, 17, 158-163. (Pubitemid 38339741)
95. Yung, L.; Huang, Y.; Lessard, P.; Legname, G.; Lin, E.; Baldwin, M.; Prusiner, S.; Ryou, C.; Guglielmo, B. J. Pharmacokinetics of quinacrine in the treatment of prion disease. BMC Infect. Dis., 2004, 4, 53.
96. Zheng, G. Z.; Bhatia, P.; Kolasa, T.; Patel, M.; El Kouhen, O. F.; Chang, R.; Uchic, M. E.; Miller, L.; Baker, S.; Lehto, S. G.; Honore, P.; Wetter, J. M.; Marsh, K. C.; Moreland, R. B.; Brioni, J. D.; Stewart, A. O. Correlation between brain/plasma ratios and efficacy in neuropathic pain models of selective metabotropic glutamate receptor 1 antagonists. Bioorg. Med. Chem. Lett., 2006, 16, 4936-4940. (Pubitemid 44175850)
97. Jadhav, S. B.; Murthy, P. S. N.; Singh, M. M.; Jain, G. K. Distribution of lovastatin to bone and its effect on bone turnover in rats. J. Pharm. Pharmacol., 2006, 58, 1451-1458. (Pubitemid 44785533)
98. Metallidis, S.; Charokopos, N.; Nikolaidis, J.; Alexiadou, E.; Lazaraki, G.; Koumentaki, E.; Tsona, A.; Theodoridis, G.; Nikolaidis, P. Penetration of moxifloxacin into sternal bone of patients undergoing routine cardiopulmonary bypass surgery. Int. J. Antimicrob. Agents, 2006, 28, 428-432. (Pubitemid 44636183)
99. Malincarne, L.; Ghebregzabher, M.; Moretti, M. V.; Egidi, A. M.; Canovari, B.; Tavolieri, G.; Francisci, D.; Cerulli, G.; Baldelli, F. Penetration of moxifloxacin into bone in patients undergoing total knee arthroplasty. J. Antimicrob. Chemother., 2006, 57, 950-954.
100. Scott, G.; Rordorf, C.; Reynolds, C.; Kalbag, J.; Looby, M.; Milosavljev, S.; Weaver, M.; Huff, J. P.; Ruff, D. A. Pharmacokinetics of lumiracoxib in plasma and synovial fluid. Clin. Pharmacokinet., 2004, 43, 467-478. (Pubitemid 38716504)
101. Koltun, D. O.; Vasilevich, N. I.; Parkhill, E. Q.; Glushkov, A. I.; Zilbershtein, T. M.; Mayboroda, E. I.; Boze, M. A.; Cole, A. G.; Henderson, I.; Zautke, N. A.; Brunn, S. A.; Chu, N.; Hao, J.; Mollova, N.; Leung, K.; Chisholm, J. W.; Zablocki, J. Orally bioavailable, liver-selective stearoyl-coa desaturase (scd) inhibitors. Bioorg. Med. Chem. Lett., 2009, 19, 3050-3053.
102. Oballa, R. M.; Belair, L.; Black, W. C.; Bleasby, K.; Chan, C. C.; Desroches, C.; Du, X.; Gordon, R.; Guay, J.; Guiral, S.; Hafey, M. J.; Hamelin, E.; Huang, Z.; Kennedy, B.; Lachance, N.; Landry, F.; Li, C. S.; Mancini, J.; Normandin, D.; Pocai, A.; Powell, D. A.; Ramtohul, Y. K.; Skorey, K.; Sørensen, D.; Sturkenboom, W.; Styhler, A.; Waddleton, D. M.; Wang, H.; Wong, S.; Xu, L.; Zhang, L. Development of a liver-targeted stearoyl-coa desaturase (scd) inhibitor (mk-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia. J. Med. Chem., 2011, 54, 5082-5096.
103. Wacke, R.; Förster, S.; Adam, U.; Mundkowski, R. G.; Klar, E.; Hopt, U. T.; Drewelow, B. Penetration of moxifloxacin into the human pancreas following a single intravenous or oral dose. J. Antimicrob. Chemother., 2006, 58, 994-999.
104. Zeitlinger, B. S.; Zeitlinger, M.; Leitner, I.; uuml; ller, M.; Joukhadar, C. Clinical scoring system for the prediction of target site penetration of antimicrobials in patients with sepsis. Clin. Pharmacokinet., 2007, 46, 75-83. (Pubitemid 46089666)
105. Barbour, A.; Schmidt, S.; Sabarinath, S. N.; Grant, M.; Seubert, C.; Skee, D.; Murthy, B.; Derendorf, H. Soft-tissue penetration of ceftobiprole in healthy volunteers determined by in vivo microdialysis. Antimicrob. Agents Chemother., 2009, 53, 2773-2776.
106. Wang, L.; Soon, G. H.; Seng, K.-Y.; Li, J.; Lee, E.; Yong, E.-L.; Goh, B.-C.; Flexner, C.; Lee, L. Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers. Antimicrob. Agents Chemother., 2011, 55, 4090-4095.
107. Ziglam, H. M.; Baldwin, D. R.; Daniels, I.; Andrews, J. M.; Finch, R. G. Rifampicin concentrations in bronchial mucosa, epithelial lining fluid, alveolar macrophages and serum following a single 600 mg oral dose in patients undergoing fibre-optic bronchoscopy. J. Antimicrob. Chemother., 2002, 50, 1011-1015. (Pubitemid 36032825)
108. Lovich, M. A.; Edelman, E. R. Tissue concentration of heparin, not administered dose, correlates with the biological response of injured arteries in vivo. Proceedings of the National Academy of Sciences, 1999, 96, 11111-11116. (Pubitemid 29487342)