Background.
Permeability glycoprotein (P-gp) is an efflux transporter that protects the body from many exogenous toxins but also blocks entry into cells of many therapeutic drugs. For example, P-gp is part of the blood-brain barrier as well as the blood-testis barrier and blocks entry of some toxins and drugs into these two organs.
Loperamide (Imodium ®) is a potent opiate agonist and is an over-the-counter anti-diarrheal drug. Loperamide acts via opiate receptors in gut to slow motility but has no effects on central nervous system, because P-gp avidly blocks its entry into brain.
In addition to being a portion of the blood-brain barrier, P-gp is expressed in many organs of the body and significantly modulates distribution, metabolism, and excretion of drugs. P-gp also plays a role in pathophysiology. Many tumors become resistant to cancer chemotherapies, and P-gp is over expressed on a high percentage of these multi-drug resistant tumors. P-gp blocks the entry of cancer chemotherapies into the cell and thereby blocks their therapeutic effects.In addition to being a portion of the blood-brain barrier, P-gp is expressed in many organs of the body and significantly modulates distribution, metabolism, and excretion of drugs. P-gp also plays a role in pathophysiology. Many tumors become resistant to cancer chemotherapies, and P-gp is over expressed on a high percentage of these multi-drug resistant tumors. P-gp blocks the entry of cancer chemotherapies into the cell and thereby blocks their therapeutic effects.In addition to being a portion of the blood-brain barrier, P-gp is expressed in many organs of the body and significantly modulates distribution, metabolism, and excretion of drugs. P-gp also plays a role in pathophysiology. Many tumors become resistant to cancer chemotherapies, and P-gp is over expressed on a high percentage of these multi-drug resistant tumors. P-gp blocks the entry of cancer chemotherapies into the cell and thereby blocks their therapeutic effects.
Legend. We injected a radiolabeled analog of loperamide into a healthy male subject and scanned the body for about two hours. The compound is the 11C–labeled metabolite of loperamide – namely, desmethyl–loperamide. P–gp is working properly in this subject, since we see no radioactivity in brain or testes. Download the movie clip that shows a 3D rotating image acquired in the first few minutes after injection of radioligand. The rotating image shows the venous sinuses surrounding the brain. P–gp exludes the radioligand from both brain and cerebrospinal fluid. In fact, P–gp is so efficient that we can see the higher concentration of radioligand in the venous drainage from brain and cerebrospinal fluid.
References. J.-S. Liow, W. Kreisl, S.S. Zoghbi, N. Lazarova, N. Seneca, R.L. Gladding, A. Taku, P. Herscovitch, V.W. Pike, and R.B. Innis. . P-glycoprotein function at the blood-brain barrier imaged using 11C-N-desmethyl-loperamide in monkeys. J. Nucl. Med., 50: 108-115, 2009. Download Reference in PDF Format (870 kb)
Nicholas Seneca, Sami S. Zoghbi, Jeih-San Liow, William Kreisl, Peter Herscovitch, Kimberly Jenko, Robert L. Gladding, Andrew Taku, Victor W. Pike, and Robert B. Innis. Human Brain Imaging and Radiation Dosimetry of 11C-N-desmethylloperamide, a Positron Emission Tomographic Radiotracer to Measure the Function of P-glycoprotein, J. Nucl. Med, 50: 807-813, 2009 Download Reference in PDF Format (510 kb)
Download Rotating Subject (.AVI) (16.5 Mb)
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