Interaction of drugs with P-glycoprotein in brain capillaries

doi:10.1016/0006-2952(95)02073-X

Biochemical Pharmacology

Volume 50, Issue 10, 9 November 1995, Pages 1701-1709

https://doi.org/10.1016/0006-2952(95)02073-X Get rights and content

Abstract

P-glycoprotein (P-gp) is expressed at high levels in a variety of non-cancerous tissues such as the endothelial cells of the blood-brain barrier (BBB) capillaries. These thin capillaries tightly regulate the movement of substrates from the circulating blood into the brain. P-gp may be involved in the exclusion of various drugs from the capillary endothelial cells, blocking their entry into the brain. However, interactions of drugs with P-gp expressed in brain capillaries remain to be characterized. We have performed photoaffinity labeling studies using [¹²⁵I]arylazidoprazosin (IAAP) to evaluate the inhibitory efficiency of various compounds. Cyclosporin A (CsA) and its derivative PSC 833 (PSC) were the most effective inhibitors of IAAP binding among the drugs tested. The magnitude of inhibition was: PSC > CsA > quinidine > vinblastine > verapamil > actinomycinD > colchicine > reserpine > bilirubin > doxorubicin > progesterone. Cremophor El, the vehicle used to administer CsA and PSC intravenously, was also able to inhibit IAAP photolabeling of P-gp. Labeling experiments were also performed using a photoactivatable [³H]CsA derivative. Photolabeling of P-gp with this compound was abolished almost completely by CsA and PSC. In vivo studies were also performed by treating rats with CsA [10 mg/(kg · day) for 10 days]. Following this treatment, no alteration in the level of P-gp expression in brain capillaries was; observed. These results suggest that, at the proper dosage, administration of CsA to cancer patients could help to enhance the response of brain tumors to chemotherapeutic agents without modifying the intrinsic level of P-gp expression in this tissue.

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Compared to control animals, PGP, ET_B receptor and p38MAPK expression was increased in the hippocampus of epileptic animals. Neither SB202190 nor BQ788 affected the spontaneous seizure activity in epileptic rats. Three of ten rats were responders and achieved complete seizure control or significant reduction in seizure activity by LEV. In four of ten rats, seizure frequency was unaltered by LEV (non-responders). LEV + SB202190 reduced seizure duration, but not seizure frequency, in both responders and non-responders. LEV + BQ788 alleviated seizure frequency and seizure duration in both responders and non-responders. Compared to responders, PGP and ET_B receptor expression was enhanced in the hippocampus of non-responders.
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Research paperInteraction of drugs with P-glycoprotein in brain capillaries

Abstract

Biochim Biophys Acta

Biochim Biophys Acta

J Biol Chem

Cell

Biochem Pharmacol

Biochem Pharmacol

Biochim Biophys Acta

Anal Biochem

Biochim Biophys Acta

J Biol Chem

J Biol Chem

Eur J Cancer

J Biol Chem

Eur J Cancer

Pharmacology of drugs that alter multidrug resistance in cancer

Pharmacol Rev

Biochemistry of multidrug resistance mediated by the multidrug transporter

Annu Rev Biochem

Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines

Science

Amplification of P-glycoprotein genes in multi-drug-resistant mammalian cell lines

Nature

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

Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: Evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein

J Histochem Cytochem

Research paper
Interaction of drugs with P-glycoprotein in brain capillaries