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Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833.
Open accessAbstract
Mice lacking mdr1-type P-glycoproteins (mdr1a/1b [-/-] mice) display large changes in the pharmacokinetics of digoxin and other drugs. Using the kinetics of digoxin in mdr1a/1b (-/-) mice as a model representing a complete block of P-glycoprotein activity, we investigated the activity and specificity of the reversal agent SDZ PSC833 in inhibiting mdr1-type P-glycoproteins in vivo. Oral PSC833 was coadministered with intravenous [3H]digoxin to wild-type and mdr1a/1b (-/-) mice. The direct excretion of [3H]digoxin mediated by P-glycoprotein in the intestinal mucosa of wild-type mice was abolished by administration of PSC833. Hepatobiliary excretion of [3H]digoxin was markedly decreased in both wild-type and mdr1a/1b (-/-) mice by PSC833, the latter effect indicating that in vivo, PSC833 inhibits not only mdr1-type P-glycoproteins, but also other drug transporters. Upon coadministration of PSC833, brain levels of [3H]digoxin in wild-type mice showed a large increase, approaching (but not equaling) the levels found in brains of PSC833-treated mdr1a/1b (-/-) mice. Thus, orally administered PSC833 can inhibit blood-brain barrier P-glycoprotein extensively, and intestinal P-glycoprotein completely. These profound pharmacokinetic effects of PSC833 treatment imply potential risks, but also promising pharmacological applications of the use of effective reversal agents.
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Cited by
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Gottesman, M. M., Fojo, T., & Bates, S. E. (2002) · Nature Reviews Cancer · doi:10.1038/nrc706 · Cited by 5,536
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Fromm, M. F. (2004) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2004.06.002 · Cited by 592
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Mizuno, N., Niwa, T., Yotsumoto, Y., & Sugiyama, Y. (2003) · Pharmacological Reviews · doi:10.1124/pr.55.3.1 · Cited by 490
Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo
Fellner, S., Bauer, B., Miller, D. S., Schaffrik, M., Fankhänel, M., Spruß, T., Bernhardt, G., Graeff, C., Färber, L., Gschaidmeier, H., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15451 · Cited by 359
Westphal, K. (2000) · Clinical Pharmacology & Therapeutics · doi:10.1067/mcp.2000.109797 · Cited by 285
Metadata
- Authors
- Mayer, U., Wagenaar, E., Dorobek, B., Beijnen, J. H., Borst, P., & Schinkel, A. H.
- Venue
- Journal of Clinical Investigation
- Published
- 1997-11-15
- Volume
- 100
- Issue
- 10
- Pages
- 2430-2436
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2087530953
- Cited by
- 269
- References
- 0
- FWCI
- 6.59
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Mayer, U., Wagenaar, E., Dorobek, B., Beijnen, J. H., Borst, P., & Schinkel, A. H. (1997). Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. Journal of Clinical Investigation. https://doi.org/10.1172/jci119784
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