Variable modulation of opioid brain uptake by P-glycoprotein in mice

doi:10.1016/j.bcp.2003.08.027

Biochemical Pharmacology

Volume 67, Issue 2, 15 January 2004, Pages 269-276

https://doi.org/10.1016/j.bcp.2003.08.027 Get rights and content

Abstract

The efflux transporter P-glycoprotein (P-gp) is an important component of the blood–brain barrier (BBB) that limits accumulation of many compounds in brain. Some opioids have been shown to interact with P-gp in vitro and in vivo. Genetic or chemical disruption of P-gp has been shown to enhance the antinociceptive and/or toxic effects of some opioids, although the extent of this phenomenon has yet to be understood. The purpose of this study was to assess quantitatively the influence of mdr1a P-gp on initial brain uptake of chemically diverse opioids in mice. The brain uptake of opioids selective for the mu (fentanyl, loperamide, meperidine, methadone, and morphine), delta (deltorphin II, DPDPE, naltrindole, SNC 121) and kappa (bremazocine and U-69593) receptor subtypes was determined in P-gp-competent (wild-type) and P-gp-deficient [mdr1a(−/−)] mice with an in situ brain perfusion model. BBB permeability of the opioids varied by several orders of magnitude in both mouse strains. The difference in brain uptake between P-gp-competent and P-gp-deficient mice ranged from no detectable effect (meperidine) to ≥8-fold increase in uptake (DPDPE, loperamide, and SNC 121). In addition, loperamide efflux at the BBB was inhibited by quinidine. These results demonstrate that P-gp modulation of opioid brain uptake varies substantially within this class of compounds, regardless of receptor subtype. P-gp-mediated efflux of opioids at the BBB may influence the onset, magnitude, and duration of analgesic response. The variable influence of P-gp on opioid brain distribution may be an important issue in the context of pharmacologic pain control and drug interactions.

Section snippets

Materials

Probe substrates were obtained from the following sources: [ $^{3} H$ ]-deltorphin II (49.5 Ci/mmol), [ $^{3} H$ ]-DPDPE (45 Ci/mmol), and [ $^{14} C$ ]-inulin (2.21 mCi/g) (NEN Life Science Products); [ $^{3} H$ ]-meperidine (3 Ci/mmol) (Moravek Biochemicals); [ $^{3} H$ ]-morphine (80 Ci/mmol) and [ $^{3} H$ ]-naltrindole (60 Ci/mmol) (American Radiolabeled Chemicals); [ $^{3} H$ ]-SNC 121 (53 Ci/mmol) (Tocris Cookson); [ $^{3} H$ ]-U-69593 (65 Ci/mmol) (Amersham Pharmacia Biotech); (±)-bremazocine, loperamide, and R-(−)-methadone (Research Biochemicals Inc.);

Time dependence of brain uptake

Brain uptake of meperidine, U-69593, naltrindole, and SNC 121 at multiple time points in P-gp-competent and P-gp-deficient mice, expressed as apparent distributional space (V_brain), is shown in Fig. 1. For these compounds, nonlinear least-squares regression of the data with Eq. (3) indicated that the egress component (Cl_eg) was negligible even in P-gp-competent mice (<10% relative to Cl_up). This indicated that brain uptake of these opioids was mostly unidirectional over 60–100 s of brain

Discussion

The results of the present study demonstrate variable P-gp modulation of opioid brain uptake by in situ brain perfusion in P-gp-competent (wild-type) and P-gp-deficient [mdr1a(−/−)] mice. Over short perfusion times, this approach estimates unidirectional influx across the intact BBB. It is important to note that it may be possible to underestimate the brain uptake if the data are outside of the linear range. However, under these experimental conditions, unidirectional uptake conditions were

Acknowledgements

Funding for this research was provided by NIH grant GM61191.

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Variable modulation of opioid brain uptake by P-glycoprotein in mice

Abstract

Section snippets

Materials

Time dependence of brain uptake

Discussion

Acknowledgements

Semin. Cancer Biol.

Adv. Drug Deliv. Rev.

Neuropharmacology

Adv. Drug Deliv. Rev.

J. Biol. Chem.

Biochem. Pharmacol.

J. Pharm. Sci.

Life Sci

Pain

Biochemical, cellular, and pharmacological aspects of the multidrug transporter

Annu. Rev. Pharmacol. Toxicol.

Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood–brain barrier sites

Proc. Natl. Acad. Sci. U.S.A.

Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier

Proc. Natl. Acad. Sci. U.S.A.

Spinal cord bioavailability of methylprednisolone after intravenous and intrathecal administration: the role of P-glycoprotein

Anesthesiology

Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A

J. Clin. Invest.

The role of P-glycoprotein in blood–brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (−/−) and mdr1a (+/+) mice

Br. J. Pharmacol.

Effect of GF120918, a potent P-glycoprotein inhibitor, on morphine pharmacokinetics and pharmacodynamics in the rat

Pharm. Res.

Effects of a potent and specific P-glycoprotein inhibitor on the blood–brain barrier distribution and antinociceptive effect of morphine in the rat

Drug Metab. Dispos.

Morphine antinociception is enhanced in mdr1a gene-deficient mice

Pharm. Res.

P-glycoprotein in the blood–brain barrier of mice influences the brain penetration and pharmacological activity of many drugs

J. Clin. Invest.

Altered disposition and antinociception of [d-penicillamine(2,5)] enkephalin in mdr1a-gene-deficient mice

J. Pharmacol. Exp. Ther.

Enhanced antinociception of the model opioid peptide [d-penicillamine] enkephalin by P-glycoprotein modulation

Pharm. Res.