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Lipophilicities of Baclofen Ester Prodrugs Correlate with Affinities to the ATP-Dependent Efflux Pump P-Glycoprotein: Relevance for Their Permeation Across the Blood-Brain Barrier?

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Abstract

Purpose. Distribution to the effect site is a prerequisite for the therapeutic effect and determined by physicochemical properties and affinities to inside- and outside-directed transporters. Based on the hypothesis that lipophilic esters of the GABA-derivative baclofen have a higher affinity to brain tissue, baclofen esters (methyl, ethyl, 1-propyl, 2-propyl, butyl) were studied regarding their penetration through the blood-brain barrier and their affinities to P-glycoprotein (P-gp).

Methods. Octanol-water distribution coefficients (D) served as lipophilicity parameters. Blood and brain concentrations of baclofen and its methyl ester were determined in vivo in rats following intraperitoneal administration. Affinities to P-gp were evaluated using a radioligand binding assay based on P-gp-overexpressing cells and [3H]-talinolol as radioligand.

Results. Log D values for baclofen and ester derivatives were -0.96 (baclofen), 0.48 (methyl), 0.77 (ethyl), 1.31 (1-propyl), 1.27 (2-propyl), and 1.42 (butyl). In-vitro studies yielded negligible affinity of baclofen to P-gp, whereas IC50-values for the esters ranged between 1300 μM (methyl) and 290 μM (2-propyl). Affinity parameters correlated well with the lipophilicity parameters.

Conclusions. Despite the P-gp affinity, brain concentrations of methyl ester were significantly higher than those of baclofen, however, baclofen levels following administration of the ester were smaller than with baclofen administration indicating only partial hydrolysis.

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REFERENCES

  1. H. Müller, J. Zierski, D. Dralle, D. Krauß, and E. Mutschler. Pharmacokinetics of intrathecal baclofen. In: H. Müller, J. Zierski, and R. D. Penn (eds.) Local-Spinal Therapy of Spasticity, Springer Verlag Berlin, Heidelberg, New York, 1988 pp. 223-226.

    Google Scholar 

  2. Y. Kido, I. Tamai, H. Uchino, F. Suzuki, Y. Sai, and A. Tsuji. Molecular and functional identification of large neutral amino acid transporters LAT1 and LAT2 and their pharmacological relevance at the blood-brain barrier. J. Pharm. Pharmacol. 53:497-503 (2001).

    Google Scholar 

  3. H. Matsuo, S. Tsukada, T. Nakata, A. Chairoungdua, D. K. Kim, S. H. Cha, J. Inatomi, H. Yorifuji, J. Fukuda, H. Endou, and Y. Kanai. Expression of a system L neutral amino acid transporter at the blood-brain barrier. NeuroReport 11:3507-3511 (2000).

    Google Scholar 

  4. I. Tamai and A. Tsuji. Transporter-mediated permeation of drugs across the blood-brain barrier. J. Pharm. Sci. 89:1371-1388 (2000).

    Google Scholar 

  5. I. A. Simpson, N. M. Appel, M. Hokari, J. Oki, G. D. Holman, F. Maher, E. M. Koehler-Stec, S. J. Vannucci, and Q. R. Smith. Blood-brain barrier glucose transporter: effects of hypo-and hyperglycemia revisited. J. Neurochem. 72:238-247 (1999).

    Google Scholar 

  6. P. Jolliet-Riant and J. P. Tillement. Drug transfer across the blood-brain barrier and improvement of brain delivery. Fundament. Clin. Pharmacol. 13:16-26 (1999).

    Google Scholar 

  7. R. J. Boado, J. Y. Li, M. Nagaya, C. Zhang, and W. M. Pardridge. Selective expression of the large neutral amino acid transporter at the blood-brain barrier. Proc. Natl. Acad. Sci. USA 96:12079-12084 (1999).

    Google Scholar 

  8. E. M. Cornford, S. Hyman, and B. E. Swartz. The human brain GLUT1 transporter: ultrastructural localization of the blood-brain barrier endothelia. J. Cereb. Blood Flow Metab. 14:106-112 (1994).

    Google Scholar 

  9. M. F. Fromm. P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int. J. Clin. Pharmacol. Ther. 38:69-74 (2000).

    Google Scholar 

  10. J. Bart, H. J. Groen, N. H. Hendrikse, W. T. van der Graaf, W. Vaalburg, and E. G. de Vries. The blood-brain barrier and oncology: new insights into function and modulation. Cancer Treat. Rev. 26:449-462 (2000).

    Google Scholar 

  11. P. L. Golden and W. M. Pardridge. Brain microvascular P-glycoprotein and a revised model of multidrug resistance in brain. Cell. Mol. Neurobiol. 20:165-181 (2000).

    Google Scholar 

  12. M. Sugawara, W. Huang, Y. J. Fei, F. H. Leibach, V. Ganapathy, and M. E. Ganapathy. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J. Pharm. Sci. 89:781-789 (2000).

    Google Scholar 

  13. R. Niemi, P. Turhanen, J. Vepsalainen, H. Taipale, and T. Jarvinen. Bisphosphonate prodrugs: synthesis and in vitro evaluation of alkyl and acylmethoxy esters of etidronic acid as bioreversible prodrugs of etidronate. Eur. J. Pharm. Sci. 11:173-180 (2000).

    Google Scholar 

  14. L. Mizen and G. Burton. The use of esters as prodrugs for oral delivery of beta-lactam antibiotics. Pharm. Biotech. 11:11345-11365 (1998).

    Google Scholar 

  15. Y. Deguchi, H. Hayashi, S. Fujii, T. Naito, Y. Yokoyama, S. Yamada, and R. Kimura. Improved brain delivery of a nonsteroidal anti-inflammatory drug with a synthetic glyceride ester: a preliminary attempt at a CNS drug delivery system for the therapy of Alzheimer's disease. J. Drug Target. 8:371-381 (2000).

    Google Scholar 

  16. B. Herber. Brain distribution of drugs-Correlation with lipophilicity and dependence on the administration route. PhD thesis, Martin-Luther-University Halle-Wittenberg, Halle/S., Department of Pharmacy (2002)

  17. S. Döppenschmitt, H. Spahn-Langguth, C. G. Regardh, and P. Langguth. The role of P-glycoprotein mediated secretion in absorptive drug fluxes. J. Pharm. Sci. 88:1067-1072 (1999).

    Google Scholar 

  18. R. C. Baselt, D. Yoshikawa, and J. Chang. and J. Li. Improved long-term stability of blood cocaine in evacuated collection tubes. J. Forensic Sci. 38:935-937 (1993).

    Google Scholar 

  19. L. Sachs. Applied Statistics. Springer-Verlag, Berlin, Heidelberg, New York, 1978.

    Google Scholar 

  20. M. J. Moll-Navarro, M. Merino, V. G. Casabo, A. Nacher, and A. Polache. Interaction of taurine on baclofen intestinal absorption: a nonlinear mathematical treatment using differential equations to describe kinetic inhibition models. J. Pharm. Sci. 85:1248-1254 (1996).

    Google Scholar 

  21. J. B. M. M. van Bree, C. D. Heijligers-Feijen, A. G. de Boer, M. Danhof, and D. D. Breimer. Stereoselective transport of baclofen across the blood-brain barrier in rats as determined by the unit impulse response methodology. Pharm. Res. 8:259-262 (1991).

    Google Scholar 

  22. 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 

  23. A. Koggel. Influence of secretory transporters on the intestinal permeability of cationic drugs. PhD. thesis, Johannes Gutenberg-University Mainz, Department of Pharmacy (2002).

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, D-06120 Hall, Saale

    Christiane Leisen, Bernd Herbert, Cornelia Dressler, Annette Koggel & Hildegard Spahn-Langguth

  2. School of Pharmacy, Johannes Gutenberg-University, Staudingerweg 5, D-55099, Mainz

    Peter Langguth

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  1. Christiane Leisen
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  2. Peter Langguth
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  3. Bernd Herbert
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  4. Cornelia Dressler
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  5. Annette Koggel
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  6. Hildegard Spahn-Langguth
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Correspondence to Hildegard Spahn-Langguth.

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Leisen, C., Langguth, P., Herbert, B. et al. Lipophilicities of Baclofen Ester Prodrugs Correlate with Affinities to the ATP-Dependent Efflux Pump P-Glycoprotein: Relevance for Their Permeation Across the Blood-Brain Barrier?. Pharm Res 20, 772–778 (2003). https://doi.org/10.1023/A:1023437603555

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