Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Agents (modulators) that reverse the in vitro resistance of tumor cells to anticancer drugs that are substrates for P-glycoprotein (Pgp, the product of the MDR1 gene) have been given to patients concurrently with anticancer drugs in an attempt to improve therapeutic response. The vast majority of investigations into these drugs indicate that Pgp modulators decrease the systemic clearance of anticancer drugs, thus potentially nonselectively increasing exposure to normal and malignant cells and thereby potentially increasing the severity and/or incidence of adverse effects associated with the anticancer therapy. Mechanisms by which Pgp modulators could alter the pharmacokinetics of the anticancer agent include competition for cytochrome P450 intestinal or liver metabolism, inhibition of Pgp-mediated biliary excretion or intestinal transport, or inhibition of renal elimination. It is suggested that administration of Pgp modulators is unlikely to improve the therapeutic index for anticancer drugs unless agents that lack significant pharmacokinetic interactions are found. Moreover, it will likely be required that there be some cancer-tissue selectivity for modulators in order to avoid collaterally increasing the sensitivity of normal Pgp-expressing tissues to the anticancer drug.
Ther Drug Monit 1996 Aug
PMID:Are the major effects of P-glycoprotein modulators due to altered pharmacokinetics of anticancer drugs? 885 49

Itraconazole strongly interacts with some drugs metabolized by cytochrome P450 3A4, for example, felodipine and lovastatin, by inhibiting their metabolism. A concomitant use of itraconazole increases the serum concentrations of digoxin, although digoxin is excreted mainly unchanged in urine. To reveal the mechanism of the itraconazole-digoxin interaction, the effect of itraconazole on the serum concentrations and urinary excretion of digoxin was studied. Ten healthy volunteers in a double-blind, randomized, two-phase crossover study received either 200 mg itraconazole or placebo orally once a day for 5 days. On day 3, each volunteer ingested a single 0.5-mg oral dose of digoxin. The serum concentrations of digoxin and its excretion into urine as well as plasma concentrations of itraconazole were determined up to 72 hours after dosing. The mean area under the serum digoxin concentration-time curve, AUC(0-72), was approximately 50% higher (P < 0.001) during the itraconazole phase than during the placebo phase. In addition, the renal clearance of digoxin decreased about 20% (P < 0.01) by itraconazole. The increases in digoxin Cmax and T(1/2) by itraconazole were not statistically significant. The decreased renal clearance of digoxin during the itraconazole phase partially explains increased concentrations of digoxin during their concomitant use and may be caused by the inhibition of P-glycoprotein-mediated digoxin secretion in the renal tubular cells.
Ther Drug Monit 1997 Dec
PMID:Itraconazole decreases renal clearance of digoxin. 942 Oct 99

The authors sought to determine the effect of concomitant peroral (PO) administration of cyclosporine (CsA) and sirolimus (SRL, rapamycin) on the tissue distributions of CsA and SRL in the rat. Groups of four adult male Wistar-Furth rats were treated for 14 days with 2.5, 5.0, or 10.0 mg CsA/kg x day. Other groups of four adult male Wistar-Furth rats were treated for 14 days with a 1-to-6.25 weight-to-weight ratio of SRL to CsA at SRL doses of 0.4, 0.8, or 1.6 mg/kg x day. Concentrations of CsA and SRL in homogenates of heart, intestinal, kidney, liver, lung, muscle, spleen, and testes were compared to those in whole blood (WB). There was a large, dose-dependent, distinctive distribution of CsA among rat tissues, as has previously been well documented. At a constant molar dose ratio, concomitant oral administration of SRL produced an approximately two-fold increase in the concentrations of CsA in rat tissues, although SRL did not change the CsA tissue-to-WB partition coefficients. Concomitant oral CsA administration produced dose-dependent increases in SRL tissue concentrations and decreases in the SRL tissue-to-WB partition coefficients. The increases in tissue and WB concentrations on coadministration of both agents may be explained either by an increase in absorption caused by competition between the two agents for binding sites on P-glycoprotein in the gut, a reduced rate of metabolism, or to an as yet unidentified elimination mechanism. The dose-independent and unchanged CsA tissue-to-WB partition coefficients suggest that SRL does not affect the equilibrium of CsA between the central and tissue compartments, namely the tissue uptake or intracellular binding. Altered values of the SRL tissue-to-WB partition coefficients suggest that, under the conditions studied, CsA disturbs the equilibrium of SRL between the central and tissue compartments.
Ther Drug Monit 1998 Apr
PMID:Relative tissue distributions of cyclosporine and sirolimus after concomitant peroral administration to the rat: evidence for pharmacokinetic interactions. 955 25

Digoxin-drug interactions are relatively common causes of digitalis toxicity. Recently, the clinical importance of the renal tubular secretion of digoxin has been proven by documenting drug interactions at this level. The authors describe a model using cultured renal tubular cell monolayers that can be used to predict drug interactions with the cardiac glycoside. This model accurately documents known clinical digoxin interactions such as those with verapamil and propafenone. The common feature of these interactions is that they involve P-glycoprotein substrates (e.g., digoxin, vincristine, vinblastine) or inhibitors (e.g., quinidine, cyclosporine). In the case of the newly described interaction of digoxin with itraconazole, the model preceded the emergence of clinical cases.
Ther Drug Monit 1998 Apr
PMID:A model for the prediction of digoxin-drug interactions at the renal tubular cell level. 955 26

Drug resistance is a major problem in cancer chemotherapy. P-glycoprotein plays a major role in multidrug resistance in cancer cells. P-glycoprotein is expressed in some normal tissues and has physiological functions. These include protecting the brain against toxic substances at the blood-brain barrier site, excreting toxic substances from the liver, kidney, and gastrointestinal tracts, and transporting steroidal hormones in the adrenal grand. Once expressed in cancer cells. P-glycoprotein effluxes a variety of anticancer drugs, such as doxorubicin, vinca alkaloids, etoposide and taxol, and thereby allows cancer cells to show resistance to these drugs.
Ther Drug Monit 1998 Oct
PMID:Therapeutic approach to drug resistant tumors. 978 Jan 38

Multidrug resistance (MDR) to anticancer drugs can be diagnosed in tumors by molecular biology techniques (expression of the MDR1 gene), by immunologic techniques (expression of P-glycoprotein), and by functional approaches (dye exclusion). Numerous studies have tried to correlate the MDR status of tumors to the clinical response to the treatment, but wide discrepancies prevented definitive conclusions. As a consequence, the routine use of these techniques is still not possible, and continuous efforts are needed for their standardization. The development of MDR modulators in the clinical setting is a promising approach that requires rigorous clinical trials, especially with sequential design of phase 2 protocols. Definitive results are still lacking concerning the interest of combining an MDR modulator to standard chemotherapy for resistant cancers.
Ther Drug Monit 1998 Oct
PMID:Resistance to anticancer drugs: are we ready to use biologic information for the treatment of patients with cancer? 978 Jan 39

Several lipophilic, cytotoxic drugs, or both, (including anticancer drugs [Vinca alkaloids, doxorubicin, cyclosporin A, and digoxin]) have proven to be actively effluxed by P-glycoprotein (P-gp) expressed at the luminal membrane of the brain capillary endothelial cells, resulting in the very low apparent blood-brain barrier (BBB) permeation of these P-gp substrates from the blood circulating to the brain. In rats inoculated with 9L-glioma cells into the brain, the endothelial cells of tumor-associated vessels allowed easy penetration of anticancer drugs (ranimustine and doxorubicin) in tumor regions, although the normal BBB function still operated at the normal brain region to provide a barrier to the accumulation of P-gp substrates. A detailed knowledge of the BBB function would be very helpful in developing improved delivery systems of anticancer drugs to brain tumors.
Ther Drug Monit 1998 Oct
PMID:P-glycoprotein-mediated efflux transport of anticancer drugs at the blood-brain barrier. 978 Jan 40

There is widespread recognition that the ingestion of a meal is associated with a number of physiologic changes (gastric pH, gastric emptying, hepatic blood flow, etc.) that can significantly alter the rate and extent of drug absorption. It is also well recognized that the components of food can alter drug absorption through alterations in drug solubility. The nutritional status of a patient can also contribute to variability in the pharmacokinetics of certain drugs. The more recent finding that grapefruit juice can increase the bioavailability of certain drugs, by reducing presystemic intestinal metabolism, has led to renewed interest in the area of 'food-drug interactions.' Particular interest has focused on the effects of the grapefruit flavonoid, naringin, and the furanocoumarin, 6',7'-dihydroxybergamottin, on the activity of intestinal CYP3A4. The possibility that grapefruit juice might affect drug absorption via an interaction with intestinal P-glycoprotein (P-gp) is also being explored. The growing use of herbal extracts and phytopharmaceuticals raises a new challenge-will the use of these products cause changes in the pharmacokinetics of 'conventional' drugs? As a case in point, consider the phytoestrogenic isoflavones, which are being promoted for a number of health benefits. Isoflavones such as genistein and daidzein can inhibit oxidative and conjugative metabolism in vitro and interact with transporters such as P-gp and the canalicular multispecific organic anion transporter. Given that P-gp and canalicular multispecific organic anion transporter are involved in the intestinal absorption and biliary excretion of a wide range of drugs and metabolites, it is reasonable to suspect that isoflavones may alter drug disposition in humans. However, this possibility has not been explored.
Ther Drug Monit 2000 Feb
PMID:Influence of dietary components on the gastrointestinal metabolism and transport of drugs. 1068 76

P-glycoprotein (Pgp), which is coded by human MDR1 (multidrug resistance) gene, is an energy-dependent efflux pump that exports its substrates out of the cell. Human Pgp is present not only in tumor cells but also in normal tissues including the kidney, liver, small and large intestine, brain, testis, and adrenal gland, and the pregnant uterus. This tissue distribution indicates that Pgp plays a significant role in excreting xenobiotics and metabolites into urine and bile and into the intestinal lumen, and in preventing their accumulation in the brain. The roles of Pgp in drug disposition include a urinary excretion mechanism in the kidney, a biliary excretion mechanism in the liver, an absorption barrier and determinant of oral bioavailability, and the blood-brain barrier that limits the accumulation of drugs in the brain. The inhibition of the transporting function of Pgp can cause clinically significant drug interactions and can also increase the penetration of drugs into the brain and the accumulation of drugs in the brain. Digoxin is a typical substrate for Pgp, which regulates the renal tubular secretion and brain distribution of digoxin. At present, potent Pgp inhibitors are being investigated in clinical trials aimed at overcoming the intrinsic or acquired multidrug resistance of human cancers. The clinical application of these Pgp inhibitors should take into consideration the physiologic function of pgp.
Ther Drug Monit 2000 Feb
PMID:Role of P-glycoprotein in drug disposition. 1068 77

Grapefruit juice (GJ), a cytochrome P450 (CYP) 3A4 inhibitor, may affect the pharmacokinetics of drugs metabolized through CYP 3A4. Losartan, an angiotensin II antagonist, is converted into its main active metabolite E3174 by CYP 3A4 and CYP 2C9. The effect of GJ on losartan pharmacokinetics was assessed in a randomized crossover trial. Losartan was given to 9 volunteers with and without GJ. Concentrations of losartan and its E3174 metabolite were determined in serum by a high-performance liquid chromatography method (HPLC). Significant differences were observed in some of the pharmacokinetic parameters of losartan and its metabolite E3174 after losartan administration with and without co-administered GJ. The lag time (time to drug appearance in serum) of losartan increased significantly with co-administered GJ. The mean residence time (MRT) and half-life (t(1/2)) of the E3174 metabolite were significantly longer and the area under the concentration--time curve (AUC) of the E3174 metabolite was significantly smaller after concomitant GJ administration. The ratio AUC(losartan)/AUC(E3174) was significantly increased after concurrent grapefruit juice intake. The increased lag time of losartan and the increased MRT and t1/2 and decreased AUC of E3174 were considered indicative of simultaneous CYP 3A4 inhibition and P-glycoprotein activation. The significantly increased AUC(losartan)/AUC(E3174) ratio, however, indicates reduced losartan conversion to E3174 by CYP 3A4 metabolism as a result of co-administered GJ.
Ther Drug Monit 2001 Aug
PMID:Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers. 1147 18


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