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      P-glycoprotein and Drug Therapy in Organ Transplantation

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      The Journal of Clinical Pharmacology

      SAGE Publications

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          Abstract

          The role of multidrug resistance and P-glycoprotein (P-gp) in the development of drug-resistant tumor cells has been extensively studied. As more knowledge on the physiological functions of P-gp has accumulated, the effects of P-gp modulation on the pharmacokinetics and the pharmacodynamics of many drugs have become apparent. Solid organ transplant recipients receive numerous medications that are substrates for P-gp. The objective of this review is to discuss the effects of P-gp modulation on the pharmacokinetics and the pharmacodynamics of immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus, and corticosteroids. Pharmacokinetic alterations may occur in drug absorption since P-gp is in the small bowel, in drug distribution since P-gp functions in the blood-brain barrier, in drug metabolism since P-gp and cytochrome P450 3A have linked functions, and in drug elimination since P-gp is in the bile canaliculi and renal tubules. A link between P-gp and organ rejection has been speculated since upregulation of the P-gp pump may restrict immunosuppressant drug entry into immunocompetent cells. A further understanding of P-gp regulation upon chronic exposure to P-gp substrates and inhibitors and the potential administration of selective P-gp inhibitors will enhance our ability to use potent immunosuppressive drugs in organ transplant patients.

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          Most cited references 40

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          Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues.

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

            We have previously shown that absence of the mouse mdr1a (also called mdr3) P-glycoprotein in mdr1a (-/-) "knockout" mice has a profound effect on the tissue distribution and elimination of vinblastine and ivermectin, and hence on the toxicity of these compounds. We show here that the mouse mdr1a and the human MDR1 P-glycoprotein actively transport ivermectin, dexamethasone, digoxin, and cyclosporin A and, to a lesser extent, morphine across a polarized kidney epithelial cell layer in vitro. Injection of these radio-labeled drugs in mdr1a (-/-) and wild-type mice resulted in markedly (20- to 50-fold) higher levels of radioactivity in mdr1a (-/-) brain for digoxin and cyclosporin A, with more moderate effects for dexamethasone (2- to 3-fold) and morphine (1.7-fold). Digoxin and cyclosporin A were also more slowly eliminated from mdr1a (-/-) mice. Our findings show that P-glycoprotein can be a major determinant for the pharmacology of several medically important drugs other than anti-cancer agents, especially in the blood-brain barrier. These results may explain a range of pharmacological interactions observed between various drugs in patients.
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              Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells.

              Hematopoietic stem cells show reduced staining with a mitochondrial fluorescent dye, rhodamine 123 (Rh-123), which was supposed to indicate decreased mitochondrial activity in these cells. Rh123 and several other fluorescent dyes are substrates for transport mediated by P-glycoprotein (P-gp), an efflux pump responsible for multidrug resistance in tumor cells. We have found that staining of human bone marrow cells with fluorescent dyes is potentiated by P-gp inhibitors and inversely correlated with P-gp expression. P-gp is expressed in practically all hematopoietic progenitor cells, including long-term culture-initiating cells. The highest levels of P-gp among the progenitors are associated with cells displaying characteristics of pluripotent stem cells. These results have implications for stem cell purification and bone marrow resistance to cancer chemotherapy.
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                Author and article information

                Journal
                The Journal of Clinical Pharmacology
                SAGE Publications
                00912700
                October 1999
                October 1999
                March 08 2013
                : 39
                : 10
                : 995-1005
                Article
                10.1177/00912709922011755
                10516933
                © 2013

                http://doi.wiley.com/10.1002/tdm_license_1.1

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