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)

Extracts of St. John's wort ( Hypericum perforatum ) became increasingly popular as easily available remedies for mild to moderate depression. Comedication with hypericum extract was recently shown to drastically reduce plasma concentration of ciclosporin, digoxin, and indinavir. We investigated the possible interaction of hypericum extract LI160 with amitriptyline. Both antidepressants have a high probability of concomitant use. Twelve patients requiring amitriptyline treatment received a single dose of hypericum extract (900 mg) at day 1, continued by a 12-to 14-day treatment with retarded amitriptyline (75 mg twice daily). Then hypericum (900 mg/day) was added for another 14 to 16 days. Steady-state pharmacokinetics of amitriptyline were compared before and after multiple-dose treatment with hypericum extract. Furthermore, comparisons were made for single-dose kinetics of hypericum-extract ingredients hypericin, pseudohypericin, and hyperforin between the first day of concomitant treatment and LI160 alone. Multiple-dose comedication with LI160 led to a statistically significant decrease in the area under the plasma concentration-time curve within one dosing interval of amitriptyline by 22% ( p = 0.03) and nortriptyline by 41% ( p = 0.002), as well as of all hydroxylated metabolites, except for 10-E-hydroxynortriptyline. Plasma levels of amitriptyline and hydroxylated metabolites gradually decreased, whereas nortriptyline concentrations were already markedly decreased after 3 days of cotreatment with hypericum. Cumulative urinary amounts of amitriptyline and metabolites decreased to the same extent as plasma concentrations upon hypericum comedication. Induction of cytochrome P-450 enzymes or drug transporters (P-glycoprotein) by St. John's wort extract may explain this pharmacokinetic interaction. Physicians should be aware of this interaction when treating patients with amitriptyline.
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PMID:Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort ( Hypericum perforatum ). 1179 42

Protease inhibitor (PI)-enhanced regimens are becoming a standard of care in therapy for HIV infection. Many important questions remain regarding the optimal use of this treatment strategy. Multiple physiologic and pathologic factors influence the pharmacokinetic and pharmacodynamic profiles of PIs. Specifically, alterations in drug metabolism associated with inhibition or stimulation of the 3A4 isozyme of the cytochrome P-450 enzyme system, activity of the P-glycoprotein intracellular transport system, and degree of plasma protein binding are all recognized as having important roles in influencing overall plasma PI concentrations and, ultimately, efficacy. Available pharmacokinetic data should include interpatient variation in plasma PI concentrations in addition to mean or median results. Viral inhibitory concentrations that have been corrected for the effect of protein binding should also be standardized. Studies to establish the concentration-response relationship for PIs may also prove beneficial in determining optimal plasma PI concentrations. Currently, therapeutic drug monitoring is not routinely recommended because of a lack of convincing clinical data as well as of a standard approach to collection and interpretation of drug concentrations. Large prospective studies are needed to further advance the usefulness of therapeutic drug monitoring.
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PMID:Pharmacokinetic enhancement of protease inhibitors. 1183 97

Herbal medications may cause prescription drug interactions in transplant recipients. After 2 of our kidney transplant recipients started self-medicating with St John's wort, their cyclosporine concentrations were consistently documented to be subtherapeutic. While on St John's wort, one patient developed acute rejection possibly due to low cyclosporine concentrations. Termination of St John's wort returned both patients' cyclosporine concentrations to therapeutic values. Based on the Naranjo Adverse Drug Reaction Probability Scale, our report would achieve a "probable" score, which supports the existence of a St John's wort-cyclosporine adverse drug interaction. St John's wort may induce cytochrome P-450 3A4 activity and/or P-glycoprotein expression, which are both involved in the metabolism and absorption of cyclosporine. Patients using St John's wort concomitantly with cyclosporine or other medications with similar absorption and/or metabolism to cyclosporine need close monitoring. Transplant coordinators are in a critical position to educate transplant recipients about the potential risks of herbal medication usage.
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PMID:St John's wort: a hidden risk for transplant patients. 1187 Oct 46

Rifampin is a potent inducer of cytochrome P-450 oxidative enzymes. A few examples of well-documented clinically significant interactions include interactions with warfarin, oral contraceptives, cyclosporine, glucocorticoids, ketoconazole or itraconazole, theophylline, quinidine sulfate, digitoxin or digoxin, verapamil hydrochloride, human immunodeficiency virus-related protease inhibitors, zidovudine, delavirdine mesylate, nifedipine, and midazolam. Recent reports have demonstrated clinically relevant interactions with numerous other drugs, such as buspirone hydrochloride, zolpidem tartrate, simvastatin, propafenone hydrochloride, tacrolimus, ondansetron hydrochloride, and opiates. Rifabutin reduces serum concentrations of antiretroviral agents, but less so than rifampin. To avoid a reduced therapeutic response, therapeutic failure, or toxic reactions when rifampin is added to or discontinued from medication regimens, clinicians need to be cognizant of these interactions. Enhanced knowledge of known interactions will continue to develop, including research on the induction of specific cytochrome P-450 isoenzymes and on the importance of the P-glycoprotein transport system. New rifampin and rifabutin interactions will be discovered with further investigations.
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PMID:Rifampin and rifabutin drug interactions: an update. 1199 7

Inhibitors of P-glycoprotein (P-gp) (verapamil) or cytochrome P-450 (ketoconazole) may reduce IL2 production and T lymphocyte proliferation in vitro. We have examined the effects of chronic oral administration of these drugs and of the cytochrome P450 inductor, carbamazepine, on the hematological and immunological parameters of mice. We found no changes after giving the mice 0.12 mg verapamil, 0.85 mg ketoconazole, or 0.514 mg carbamazepine per mouse for 4 weeks (5 days/week). But giving the drugs for an additional 7 weeks at 0.6 mg (verapamil), 4.25 mg (ketoconazole) or 2.57 mg/mouse (carbamazepine), resulted in significant decreases in monocytes in the verapamil treated group (-51%) and in CD4+ cells in the carbamazepine group (-35%). Chronic oral administration of these drugs reduced the lymphocyte counts of mice by 10-18% and their NK counts by 10-16%. These changes could be due to changes in P-gp function in the transport of IL2, with decreases caused by verapamil and ketoconazole.
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PMID:Chronic administration of verapamil, ketoconazole and carbamazepine: impact on immunological parameters. 1199 17

Several forms of cytochrome P-450 (CYP) metabolize R,S-warfarin in a regio- and enantioselective manner, therefore R,S-warfarin can be recognized as a metabolic probe for a number of CYP isoforms. We have applied a warfarin model in vivo in order to estimate the inhibitory properties of 5- and 8-methoxypsoralens on the activity of rat CYP isoforms. The area under the serum concentration versus time curve (AUC) values from time zero to 5 h for R- and S-warfarin and their metabolites were calculated. R,S-Warfarin kinetics measurements were made three times on each rat: a week before the 7-days inhibitor treatment, 3 h after the last dose of inhibitor and 3-7 days after the inhibitor was withdrawn. The inhibitory effect of cimetidine on CYP 2C11 and CYP 2C6 activities was confirmed in this approach and can be recognized as a positive control in validation of the in vivo experiment. Both 5- and 8-methoxypsoralen inhibited CYP 2C6 activity as the respective AUC for metabolite/warfarin enantiomer ratio decreased significantly. The activity of CYP 2C6 in 5- and 8-methoxypsoralen-treated rats increased over control values after the inhibitor was withdrawn. It was also observed that cimetidine additionally inhibits the absorption of R,S-warfarin and a decrease in the sum of AUC for R- and S-enantiomers became evident in spite of inhibition of the activity of both CYPs. 5-Methoxypsoralen modified the serum R-warfarin/S-warfarin ratio and a selective increase in AUC(S-warfarin) was observed, the most pronounced being after the inhibitor was withdrawn. This effect is not likely to be mediated by P-glycoprotein (P-gp) because quinidine--, a P-gp inhibitor at a dose of 15 mg kg(-1) body wt.--did not influence the AUC for either enantiomer.
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PMID:In vivo effect of 5- and 8-methoxypsoralens and cimetidine on R,S-warfarin metabolism in rat. 1235 62

We evaluated levels of intestinal expression of absorptive-barrier P-glycoprotein (PGP) and cytochrome P-450 IIIA4 (CYP3A4) and immunosuppressant therapy in a patient who underwent living donor liver transplantation (LDLT) and received a second living donor liver transplant after chronic rejection of the first. PGP and CYP3A4 expression were measured using part of a Roux-en-Y limb. After the first LDLT, the concentration-dose ratio of orally administered tacrolimus was 159.8 +/- 125.3 (average +/- SD of 32 different days), similar to the average for 46 recipients of living donor liver transplants in our hospital (161.3 +/- 88.1). However, the recipient required very large oral doses of cyclosporine (703.9 +/- 385.4 mg/d, average +/- SD of 13 different days) after the second LDLT. Although intestinal PGP level was increased markedly at the second LDLT, CYP3A4 level was decreased. In addition, levels of messenger RNA expression of several gene products related to the local inflammation, such as cyclooxygenase 2, interleukin-1beta (IL-1beta), IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha, were increased. These results suggest that hepatic failure after LDLT, including chronic rejection and/or cholangitis, was accompanied by upregulation of intestinal PGP expression, which could depress the bioavailability of the immunosuppressant.
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PMID:Enhanced expression of enterocyte P-glycoprotein depresses cyclosporine bioavailability in a recipient of living donor liver transplantation. 1452 9

The disposition of many drugs is altered in patients with acute (AKD) and chronic kidney disease (CKD). A decline in renal clearance of several drugs has been correlated significantly with residual renal function (ie, creatinine clearance) of subjects. Reductions in nonrenal clearance of some compounds also have been reported and associated with clearance of markers of oxidative and/or conjugative metabolism or P-glycoprotein-mediated transport. Although initial accounts of reduced hepatic microsomal cytochrome P-450 (CYP) content and activity in animal models of AKD and CKD were published almost 25 years ago, it is only in the last decade that technical advances in molecular biology and clinical pharmacology have enabled researchers to begin to characterize the phenotypic expression of individual enzymes and, importantly, distinguish the molecular and/or genetic basis for these changes. The selective modulation of hepatic CYP enzyme activity observed in kidney disease is caused, at least in part, by differentially altered expression of several CYP isoforms. This review summarizes data available through June 2003 regarding the effect of AKD and CKD on drug metabolism. Knowledge of the impact and nature of these alterations associated with kidney disease may facilitate the individualization of medication management in this patient population.
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PMID:Hepatic drug metabolism and transport in patients with kidney disease. 1458 35

More than a decade has passed since it was unintentionally discovered that grapefruit juice interacts with certain drugs. The coadministration of these drugs with grapefruit juice can markedly elevate drug bioavailability, and can alter pharmacokinetic and pharmacodynamic parameters of the drug. The predominant mechanism for this interaction is the inhibition of cytochrome P-450 3A4 in the small intestine, resulting in a significant reduction of drug presystemic metabolism. An additional mechanism is, presumably, the inhibition of P-glycoprotein, a transporter that carries drug from the enterocyte back to the gut lumen, resulting in a further increase in the fraction of drug absorbed. Some calcium channel antagonists, benzodiazepines, HMG-CoA reductase inhibitors and cyclosporine are the most affected drugs. A single exposure to one glass of the juice can usually produce the maximal magnitude of the interaction. The data available so far, concerning this interaction and its clinical implications, are reviewed in this article. It is likely that more information regarding this interaction will accumulate in the future, and awareness of such is necessary for achieving optimal drug therapy.
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PMID:Food-drug interaction: grapefruit juice augments drug bioavailability--mechanism, extent and relevance. 1467 60

Polymorphisms in genes can lead to differences in the level of susceptibility of individuals to potentially adverse effects of environmental influences, such as chemical exposure, on prenatal development or male or female reproductive function. We have reviewed the literature in this area, with the caveat that papers involving straight gene knock-outs in experimental animals, without a clear human relevance, were largely excluded. This review represents current knowledge in this rapidly moving field, presenting both human epidemiological and animal data, where available. Among the polymorphic genes and environmental interactions discussed with respect to prenatal development are those for P-glycoprotein (multidrug resistance protein) and the avermectins; methylenetetrahydrofolate reductase (MTHFR), an enzyme in folate metabolism, and dietary folic acid; transforming growth factor alpha (TGFalpha) and cigarette smoke; and alcohol dehydrogenase (ADH) and cytochrome P-450 (CYP) 2E1 in association with alcohol consumption. Effects on male reproduction attributable to gene-environment interaction involve infertility seen as a result of either organophosphorous (OP) pesticide interaction with the polymorphic paraoxonase (PON1) gene or antiandrogenic agent interaction with the androgen receptor (AR). MTHFR, folate metabolism, and dietary folic acid are also considered in conjunction with preeclampsia and early pregnancy loss, and the effect of the interaction of glutathione S-transferase (GST) with exposure to benzene or cigarette smoke on pregnancy maintenance is explored. As a conclusion, we offer a discussion of lessons learned and suggested research needs.
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PMID:Gene-environment interactions: a review of effects on reproduction and development. 1560 83


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