Cyclosporin A treatment induces overexpression of P-glycoprotein in the kidney and other tissues

Abstract

To see whether P-glycoprotein (PGP) expressed in renal brush-border membranes (BBM) could interact with compounds known as modulators of multidrug resistance (MDR), photoaffinity-labeling experiments were performed. A 145k-Da protein was photolabeled with [125I] iodoarylazidoprazosin, and this labeling was reduced in the presence of cyclosporin A (CsA) and PSC-833 (PSC). Interaction of CsA with PGP was further investigated by treating rats with daily subcutaneous injections of CsA (10 mg.kg-1.day-1). After this treatment, PGP expression levels were dramatically increased in renal BBM, intestine, liver, and many other tissues except the brain. This induction was a reversible process, since after cessation of CsA administration PGP levels declined to reach values similar to those of the control groups. The increase in PGP expression in the kidney was also detected in photolabeling experiments, suggesting the induction of a functional PGP. A higher dose of CsA (50 mg/kg) given as a bolus injection did not modify PGP expression] in renal BBM. These results demonstrate that CsA induces reversible overexpression of PGP in the rat. This may present significant relevance in the design of clinical trials using CsA as a chemosensitizing agent.

Oxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats

“…16,18 In this study, oxycodone had an efflux ratio of 2.06 that was decreased to 1.01 by verapamil, and significantly higher oxycodone brain levels were observed for mdr1a/b (−/−) versus mdr1a/b (+/+) mice. Finally repeated administration of oxycodone resulted in upregulation of P-gp and also affected the accumulation of the well-known P-gp substrate, paclitaxel in the liver, kidney, and brain tissues of oxycodone tolerant rats.…”

“…4,6,15,38 P-gp substrates such as morphine, cyclosporin A, vincristine, dexamethasone, and rhodamine 123 are known to induce the level of expression of P-gp upon chronic administration. 16,18 As such, it would be expected that repeated administration of P-gp substrates that are opioid agonists will markedly increase the P-gp expression. In fact, when morphine was administered to Sprague Dawley rats, a twofold increase in brain P-gp expression was observed in morphine-treated rats when compared to saline-treated rats.…”

“…Oxycodone has been used effectively for over 90 years, but unlike other opioid agonists little is known about its P-gp affinity status (substrate, inducer, or inhibitor). Chronic administration of morphine and other P-gp substrates, e.g., cyclosporin A and dexamethasone resulted in upregulation of P-gp, 16,18 whether P-gp is upregulated upon repeated administration of oxycodone is yet to be elucidated. For the management of cancer, oxycodone is usually coadministered with many chemotherapeutic agents, the majority of these agents are P-gp substrates.…”

Calcineurin Inhibitor Nephrotoxicity

“…In 1997, del Moral et al suggested that variability in local P-glycoprotein expression is important for chronic CNI nephrotoxicity by using immunohistochemistry and Western blotting in a rat model of chronic CNI nephrotoxicity (286). Another study in rats showed that exposure of cultured renal tubular cells to cyclosporine induces P-glycoprotein overexpression (287). In addition, del Moral et al demonstrated that the up-regulation of P-glycoprotein was inversely related to the incidence of arteriolar hyalinosis, interstitial fibrosis, and periglomerular fibrosis (286).…”

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

“…31 This may also be a potential mechanism for the induction of multidrug resistance through PGP upregulation. To complicate matters further, (a) induction of PGP by drugs is tissue-dependent, and this may have some bearing upon the relevance of particular inducers in the study of drug resistance in different diseases 32 ; and (b) it is also possible that baseline or constitutive expression levels may determine the maximal degree of induction that occurs in response to contact with an environmental inducer. Furthermore, the extent of induction of proteins by drugs is frequently dose-dependent and therefore differences in intracellular concentrations of inducing drugs between individuals may contribute to differences in PGP expression levels.…”