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)

During the past several years, important advances have been made in our understanding of the mechanisms that regulate the expression of genes that determine drug clearance, including phase I and phase II drug-metabolising enzymes and drug transporters. Orphan nuclear receptors have been recognised as key mediators of drug-induced changes in both metabolism and efflux mechanisms. In this review, we summarise recent findings regarding the function of nuclear receptors in regulating drug-metabolising and transport systems, and the relevance of these receptors to clinical drug-drug interactions and the development of new drugs. Emphasis is given to two newly recognised 'orphan' receptors (the pregnane X receptor [PXR] and the constitutive androstane receptor [CAR]) and their regulation of cytochrome P450 enzymes, such as CYP3A4, CYP2Cs and CYP2B6; and transporters, such as P-glycoprotein (MDR1), multidrug resistance-associated proteins (MRPs) and organic anion transporter peptide 2 (OATP2). Although 'cross-talk' occurs between these two receptors and their target sequences, significant species differences exist between ligand-binding and activation profiles for both receptors, and PXR appears to be the predominant or 'master' regulator of hepatic drug disposition in humans. Several important physiological processes, such as cholesterol synthesis and bile acid metabolism, are also tightly controlled by certain ligand-activated orphan nuclear receptors (farnesoid X receptor [FXR] and liver X receptor [LXR]). In general, their ability to bind a broad range of ligands and regulate an extensive array of genes that are involved in drug clearance and disposition makes these orphan receptors attractive targets for drug development. Drugs have the capacity to alter nuclear receptor expression (modulators) and/or serve as ligands for the receptors (agonists or antagonists), and thus can have synergistic or antagonistic effects on the expression of drug-metabolising enzymes and transporters. Coadministration of drugs that are nuclear receptor agonists or antagonists can lead to severe toxicity, a loss of therapeutic efficacy or an imbalance in physiological substrates, providing a novel molecular mechanism for drug-drug interactions.
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PMID:Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. 1467 87

Trabectedin [Ecteinascidin 743, Yondelis, ET 743, NSC 684766] is a tetrahydroisoquinoline alkaloid derived from the Caribbean marine tunicate, Ecteinascidia turbinata. The drug is being developed by PharmaMar (Zeltia) in partnership with Johnson & Johnson Pharmaceutical Research & Development LLC. It was synthetically isolated and developed by the University of Illinois and licensed to PharmaMar; the company has completed the hemisynthesis of agent. Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G(2) phase, while cells at the G(1 )phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications. PharmaMar and Ortho Biotech Products (Johnson & Johnson) entered into an agreement in August 2001 for the joint development and commercialisation of trabectedin. PharmaMar retains commercialisation rights in Europe, including Eastern Europe. Ortho Biotech will market the product in the US, Japan and the rest of the world; Tibotec Therapeutics (a division of Ortho Biotech) will commercialise it in the US. PharmaMar will receive an initial payment from Ortho Biotech plus future milestone and royalty payments linked to development targets and sales; the upfront payment would be approximately 20 million US dollars with royalties contributing 10-20% of total sales of the drug. Although details of the licensing transaction for trabectedin were undisclosed, analysts estimate the figure to be around 100 million US dollars. Previously, PharmaMar signed an agreement granting Bristol-Myers Squibb the option to evaluate and develop as many as 12 of PharmaMar's marine-derived anticancer compounds on an exclusive worldwide basis. However, it appears that Bristol-Myers Squibb had chosen not to exercise the option. Trabectedin is undergoing clinical trials in soft tissue sarcoma (Sarcoma in the Phase table), ovarian, breast, endometrial, prostate and non-small-cell lung cancers. PharmaMar indicated in January 2004 that it intends to launch trabectedin in one of these indications in 2006. PharmaMar raised funds from a round of financing in June 2005 that will be used to fund further clinical trials of its anticancer products, including trabectedin. The US FDA granted trabectedin orphan drug status for ovarian cancer in April 2005. Trabectedin also received orphan drug status from the European Commission for the treatment of ovarian cancer in October 2003. This followed a positive opinion by the Committee for Orphan Medicinal Products (COMP) of the EMEA. Trabectedin has undergone a phase II study for the second- or third-line treatment of ovarian cancer in Europe (England and Belgium), the US and Canada. The trial was initiated in October 2002 and evaluated a weekly schedule of trabectedin (0.58 mg/m(2)) via IV infusion for 3 weeks followed by a week of rest. Final results from this study have been presented. A separate phase II trial evaluating the antitumour activity of trabectedin as a second-line therapy in advanced ovarian cancer was conducted by researchers at the Southern Europe New Drugs Organization (SENDO) in Milan, Italy. PharmaMar and Johnson & Johnson are conducting a pivotal (STS-201) trial to compare a weekly and daily dosing regimen of trabectedin among patients with advanced or metastatic soft tissue sarcoma who are unresponsive to standard chemotherapy of doxorubicin and ifosfamide. The randomised, multicentre, open-label trial has completed enrolment of 270 patients during the second quarter of 2005. Positive data from the STS-201 trial have been announced. An independent data monitoring committee has found that interim data supports a positive trend in time to disease progression favouring patients receiving the daily dosing regimen. Consequently, all patients have been offered the option of switching to the daily regimen. Final results from the STS-201 trial will form the basis of MAA re-submission with European regulatory authorities. PharmaMar has held a pre-submission meeting with the EMEA and has presented a formal letter of intent to file for approval of trabectedin for soft tissue sarcoma. Previously, PharmaMar first filed for EU registration of trabectedin for treatment of advanced soft tissue sarcoma in November 2001, which was accepted for review by the EMEA and Swiss Health Authorities. However, the CPMP confirmed its recommendation not to grant trabectedin marketing authorisation in November 2003 following PharmaMar's appeal against the CPMP's negative opinion first announced in July 2003; the opinion was adopted by a majority vote rather than by consensus. Trabectedin was granted orphan drug status in Europe for recurrent soft tissue sarcoma in 2001. It was also granted orphan drug status by the FDA for the same indication in October 2004. Phase I studies are being conducted to evaluate trabectedin in combination with doxorubicin and liposomal doxorubicin for the treatment of soft tissue sarcoma. PharmaMar is also conducting a phase I study of sequential paclitaxel followed by trabectedin in patients with soft tissue sarcoma. At additional dose levels, patients with other tumour types will be enrolled to assess the antitumour activity of the combination. The US NCI has approved and is partially funding a phase I clinical programme to determine the feasibility of using trabectedin to treat children with soft tissue sarcoma and bone sarcoma who are resistant to conventional therapies. PharmaMar has reported that trabectedin can be safely administered to children at doses up to 1100mg given as a 3-hour infusion, and that this dose will be used in further paediatric studies. Trabectedin has completed phase II studies for small round cell sarcoma and rhabdomyosarcoma, which are aggressive tumours occurring predominantly in children. A phase II study evaluating two dosing schedules of trabectedin has been conducted in patients with leiomyosarcomas or liposarcomas refractory to standard doxorubicin + ifosfamide chemotherapy. The study was conducted in Australia, Canada, Russia and the US.
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PMID:Trabectedin: Ecteinascidin 743, Ecteinascidin-743, ET 743, ET-743, NSC 684766. 1692 93

Blood-brain barrier efflux transporters limit the brain penetration and efficacy of various central nervous system drugs. In several CNS diseases, therapy- or pathophysiology-associated transcriptional activation of efflux transporters further strengthens the barrier function. Targeting the regulatory pathways that drive efflux transporter expression in different diseases represents an intriguing approach for prevention of these events thereby promoting delivery to the brain and enhancing or restoring drug efficacy. In particular, the approach holds the promise to preserve basal transporter expression and activity, which is of specific relevance in view of the protective function of efflux transport. The elucidation of the signaling cascades involved in transporter regulation is a major presupposition for the development of preventive strategies. Orphan nuclear receptors as well as the Wnt/beta-catenin signaling pathway have been implicated in drug-induced changes in transporter expression. Targeting these xenobiotic sensors is therefore discussed as a means to optimize brain delivery and therapeutic outcome. Relevant progress has also been made with the identification of key signaling events that drive P-glycoprotein expression in response to pathophysiological mechanisms. In the epileptic brain, complex signaling events involving cyclooxygenase-2 activity trigger P-glycoprotein expression in response to glutamate release and activation of endothelial NMDA receptors. Moreover, reactive oxygen species and inflammatory cytokines have been identified as regulatory factors which might affect P-glycoprotein in several CNS diseases. Recent data substantiated several interesting targets in the respective signaling cascades thereby rendering a basis for the ongoing development of innovative approaches to optimize central nervous system drug brain penetration and efficacy.
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PMID:Targeting regulation of ABC efflux transporters in brain diseases: a novel therapeutic approach. 1989 2