Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs. Export

@article{citeulike:2192604, abstract = {Erratic or unpredictable response to drugs remains a challenge of modern drug therapy. An important determinant of such interindividual differences in drug response is variability in the expression of drug-metabolizing enzymes and/or transporters at sites of absorption and/or tissue distribution. Variable drug-metabolizing enzyme and transporter expression can result in unpredictable exposure and tissue distribution of drugs and may manifest as adverse effects or therapeutic failure. In the past decade, important new insights have been made relating to the regulatory mechanisms governing the expression of drug-metabolizing enzymes and transporters by ligand-activated nuclear receptors. Specifically, there is compelling evidence to demonstrate that PXR, CAR, FXR, LXR, VDR, HNF4alpha, and AhR form a battery of nuclear receptors that regulate the expression of many important drug-metabolizing enzyme and transporters. In this review, the authors focus on clinically important drug-metabolizing enzymes such as CYP3A4, CYP2B6, CYP2C9, CYP2C19, UGT1A1, SULT2A1, and glutathione S-transferases and their regulation by nuclear receptors. They also review the nuclear receptor-mediated regulation of drug transporters such as MDR1, MRP2, MRP4, BSEP, BCRP, NTCP, OATP1B3, and OATP1A2. Finally, they outline how the drug development process has been affected by the current understanding of the involvement of nuclear receptors in the regulation of drug disposition genes.}, address = {Division of Clinical Pharmacology, London Health Sciences Centre-University Hospital, Room ALL-152, 339 Windermere Road, London, Ontario N6A 5A5, Canada.}, author = {Urquhart, B. L. and Tirona, R. G. and Kim, R. B.}, citeulike-article-id = {2192604}, citeulike-linkout-0 = {http://dx.doi.org/10.1177/0091270007299930}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/17442683}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=17442683}, doi = {10.1177/0091270007299930}, issn = {0091-2700}, journal = {J Clin Pharmacol}, keywords = {drugs, hnf4, toxicology}, month = {May}, number = {5}, pages = {566--578}, posted-at = {2008-01-03 23:18:50}, priority = {2}, title = {Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs.}, url = {http://dx.doi.org/10.1177/0091270007299930}, volume = {47}, year = {2007} }

TY - JOUR ID - citeulike:2192604 L3 - citeulike-article-id:2192604 N2 - Erratic or unpredictable response to drugs remains a challenge of modern drug therapy. An important determinant of such interindividual differences in drug response is variability in the expression of drug-metabolizing enzymes and/or transporters at sites of absorption and/or tissue distribution. Variable drug-metabolizing enzyme and transporter expression can result in unpredictable exposure and tissue distribution of drugs and may manifest as adverse effects or therapeutic failure. In the past decade, important new insights have been made relating to the regulatory mechanisms governing the expression of drug-metabolizing enzymes and transporters by ligand-activated nuclear receptors. Specifically, there is compelling evidence to demonstrate that PXR, CAR, FXR, LXR, VDR, HNF4alpha, and AhR form a battery of nuclear receptors that regulate the expression of many important drug-metabolizing enzyme and transporters. In this review, the authors focus on clinically important drug-metabolizing enzymes such as CYP3A4, CYP2B6, CYP2C9, CYP2C19, UGT1A1, SULT2A1, and glutathione S-transferases and their regulation by nuclear receptors. They also review the nuclear receptor-mediated regulation of drug transporters such as MDR1, MRP2, MRP4, BSEP, BCRP, NTCP, OATP1B3, and OATP1A2. Finally, they outline how the drug development process has been affected by the current understanding of the involvement of nuclear receptors in the regulation of drug disposition genes. IS - 5 JF - J Clin Pharmacol SN - 0091-2700 AD - Division of Clinical Pharmacology, London Health Sciences Centre-University Hospital, Room ALL-152, 339 Windermere Road, London, Ontario N6A 5A5, Canada. EP - 578 TI - Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs. VL - 47 SP - 566 KW - drugs KW - hnf4 KW - toxicology AU - Urquhart, BL AU - Tirona, RG AU - Kim, RB PY - 2007/05// UR - http://dx.doi.org/10.1177/0091270007299930 ER -