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Effects of a Potent and Specific P-Glycoprotein Inhibitor on the Blood-Brain Barrier Distribution and Antinociceptive Effect of Morphine in the Rat
Abstract
Previous data suggest that the analgesic effect of morphine may be modulated by P-glycoprotein (P-gp) inhibition. The effects of the P-gp inhibitor GF120918 on brain distribution and antinociceptive effects of morphine were examined in a rat cerebral microdialysis model. Pretreatment with GF120918 increased both the area under the concentration-time curve of unbound morphine in brain extracellular fluid (ECF) and morphine-associated antinociception. The area under the concentration-time curve ratio for unbound morphine in brain ECF versus unbound morphine in blood was significantly higher in GF120918-treated rats compared with control rats (1.21 +/- 0.34 versus 0.47 +/- 0.05, respectively; p <.05). Modulation of morphine brain-blood distribution was confirmed by quantitating brain tissue morphine in a separate group of rats; GF120918 increased the brain tissue:serum concentration ratio approximately 3-fold. The half-life of unbound morphine in brain ECF was approximately 3-fold longer in GF120918-treated rats compared with controls (p <.05). The fraction unbound of morphine in whole blood was not altered significantly in the presence of GF120918 (0.651 +/- 0.039) as compared with controls (0.662 +/- 0.035). Concentrations of unbound morphine-3-glucuronide in blood and brain ECF were increased in GF120918-treated rats versus controls. An integrated pharmacokinetic/pharmacodynamic model was developed to characterize the unbound blood and brain ECF morphine concentration profiles and concentration-effect relationships. The results of this study indicate that alteration of morphine antinociception by a potent P-gp inhibitor appears to be mediated at the level of the blood-brain barrier.
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Cites
Lipid solubility and drug penetration of the blood brain barrier
Oldendorf, W. H. (1974) · Experimental Biology and Medicine · doi:10.3181/00379727-147-38444 · Cited by 373
Cited by
Blood-brain barrier active efflux transporters: ATP-binding cassette gene family
Löscher, W., & Potschka, H. (2005) · NeuroRX · doi:10.1602/neurorx.2.1.86 · Cited by 872
Doran, A., Obach, R. S., Smith, B. J., Hosea, N. A., Becker, S., Callegari, E., Chen, C., Chen, X., Choo, E., Cianfrogna, J., et al. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.104.001230 · Cited by 443
Role of transport proteins in drug absorption, distribution and excretion
Ayrton, A., & Morgan, P. (2001) · Xenobiotica · doi:10.1080/00498250110060969 · Cited by 421
Shitara, Y., Maeda, K., Ikejiri, K., Yoshida, K., Horie, T., & Sugiyama, Y. (2013) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.1823 · Cited by 418
Regulation of Drug-Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer
Morgan, E. T., Goralski, K. B., Piquette-Miller, M., Renton, K. W., Robertson, G. R., Chaluvadi, M. R., Charles, K. A., Clarke, S. J., Kacevska, M., Liddle, C., et al. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.107.018747 · Cited by 395
Metadata
- Authors
- Letrent, S. P., Pollack, G. M., Brouwer, K. R., & Brouwer, K. L. R.
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 1999-07
- Volume
- 27
- Issue
- 7
- Pages
- 827-834
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2144497954
- Cited by
- 169
- References
- 1
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- closed
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- CoChat. (2026). Citation check: Effects of a Potent and Specific P-Glycoprotein Inhibitor on the Blood-Brain Barrier Distribution and Antinociceptive Effect of Morphine in the Rat. https://app.cochat.ai/papers/10.1016/s0090-9556(24)11822-3
- The paper
- Letrent, S. P., Pollack, G. M., Brouwer, K. R., & Brouwer, K. L. R. (1999). Effects of a Potent and Specific P-Glycoprotein Inhibitor on the Blood-Brain Barrier Distribution and Antinociceptive Effect of Morphine in the Rat. Drug Metabolism and Disposition. https://doi.org/10.1016/s0090-9556(24)11822-3
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
