Irradiation of rat brain reduces P-glycoprotein expression and function

Abstract

The blood -brain barrier (BBB) hampers delivery of several drugs including chemotherapeutics to the brain. The drug efflux pump P-glycoprotein (P-gp), expressed on brain capillary endothelial cells, is part of the BBB. P-gp expression on capillary endothelium decreases 5 days after brain irradiation, which may reduce P-gp function and increase brain levels of P-gp substrates. To elucidate whether radiation therapy reduces P-gp expression and function in the brain, right hemispheres of rats were irradiated with single doses of 2 -25 Gy followed by 10 mg kg À1 of the P-gp substrate cyclosporine A (CsA) intravenously (i.v.), with once 15 Gy followed by CsA (10, 15 or 20 mg kg À1 ), or with fractionated irradiation (4 Â 5 Gy) followed by CsA (10 mg kg À1 ) 5 days later. Additionally, four groups of three rats received 25 Gy once and were killed 10, 15, 20 or 25 days later. The brains were removed and P-gp detected immunohistochemically. P-gp function was assessed by [ 11 C]carvedilol uptake using quantitative autoradiography. Irradiation increased [11 C]carvedilol uptake dose-dependently, to a maximum of 20% above non irradiated hemisphere. CsA increased [ 11 C]carvedilol uptake dose-dependently in both hemispheres, but more (Po0.001) in the irradiated hemisphere. Fractionated irradiation resulted in a lost P-gp expression 10 days after start irradiation, which coincided with increased [ 11 C]carvedilol uptake. P-gp expression decreased between day 15 and 20 after single dose irradiation, and increased again thereafter. Rat brain irradiation results in a temporary decreased P-gp function.

Summary of Information on the Effects of Ionizing and Non-ionizing Radiation on Cytochrome P450 and Other Drug Metabolizing Enzymes and Transporters

“…However, fractionated radiation with X-rays resulted in decreased P-gp protein expression, and consequently the drug sensitivity of multidrug-resistant (MDR) cells was enhanced [33]. Using functional analysis, immunohistochemistry, and immunoblotting (following irradiation by either single doses of X-rays up to 25 Gy or fractionated radiation of rat blood-brain barrier), decreased P-gp protein expression and activity were observed [34,35], suggesting that in some cases radiation might be used to enhance the delivery of P-gp substrates to the brain. This result further shows that predictions of the irradiation effects are rather difficult and complex in nature.…”

SPECT and PET Imaging of Multidrug Resistance

“…P-gp expression decreased between day 15 and 20 after single-dose irradiation, and increased again thereafter. 51 These studies both indicate that radiotherapy influences both P-gp expression and P-gp function.…”

“…We irradiated the right brain hemisphere of rats with single fractions of radiotherapy to elucidate whether radiation therapy reduced P-gp expression and function in the brain, as measured with the P-gp substrate 11 C-carvedilol. 51 The right hemispheres received single doses of 2-25 Gy followed by 10 mg/kg of the P-gp substrate cyclosporin iv, with once 15 Gy followed by cyclosporin, or with fractionated irradiation (4 × 5 Gy) followed by cyclosporin five days later. Irradiation increased 11 C-carvedilol uptake dose-dependently, to a maximum of 20% above non-irradiated hemisphere.…”

Activity of Eribulin Mesylate in Brain Metastasis from Breast Cancer: A Stone in a Pond?

“…Chemotherapeutic agents do not easily cross the blood-brain barrier, while radiation therapy is known to compromise the barrier function [15] by reducing the expression of the efflux transporter P-glycoprotein [16]. Evidence suggests that this effect may last for as long as several years after postradiation therapy [15].…”