Open AccessJournal Article
Distribution of 4-Hydroxy-N-desmethyltamoxifen and Other Tamoxifen Metabolites in Human Biological Fluids during Tamoxifen Treatment
Ernst A. Lien,Einar Solheim,Oscar A. Lea,Steinar Lundgren,Stener Kvinnsland,Per Magne Ueland +5 more
Reads0
Chats0
TLDR
Several metabolites of tamoxifen, including 4-hydroxylated, conjugated metabolites (Y, B, and BX), and N-desdimethyltamxifen (metabolite Z) were identified and their concentrations determined in fluids and feces from patients receiving chronic tamox ifen treatment, suggesting that the serum levels are production rate limited.Abstract:
Several metabolites of tamoxifen, including 4-hydroxy-N-desmethyltamoxifen (metabolite BX), 4-hydroxytamoxifen (metabolite B), N-desmethyltamoxifen (metabolite X), the primary alcohol (metabolite Y), and N-desdimethyltamoxifen (metabolite Z) were identified and their concentrations determined in fluids and feces from patients receiving chronic tamoxifen treatment. The biological samples investigated were serum, pleural, pericardial and peritoneal effusions, cerebrospinal fluid, saliva, bile, feces, and urine. In serum, tamoxifen itself, and the metabolites X and Z were the prevailing species, but significant amounts of the metabolites Y, B, and BX were also detected. About 3 h after drug intake tamoxifen as well as Y, B, BX, X, and Z showed a peak in serum. This may be explained by efficient metabolism of the metabolite precursor before being distributed to peripheral compartments. Upon drug withdrawal all metabolites showed first-order elimination curves which paralleled that of tamoxifen suggesting that their rate of elimination exceeded that of tamoxifen and that the serum levels are production rate limited. The protein binding of tamoxifen and its major serum metabolites (Y, X, Z) was determined and found to be higher than 98%. Albumin was the predominant carrier for tamoxifen in human plasma. The concentrations of tamoxifen and its metabolites in pleural, pericardial, and peritoneal effusions equalled those detected in serum, corresponding to an effusion/serum ratio between 0.2 and 1. Only trace amounts of tamoxifen and metabolite X were detected in cerebrospinal fluid (CSF/serum ratio less than 0.02). In saliva, concentrations of tamoxifen and X exceeded the amounts of free drug in serum, suggesting active transport or trapping of these compounds in the salivary gland. Bile and urine were rich in the hydroxylated, conjugated metabolites (Y, B, and BX), whereas in feces unconjugated metabolite B and tamoxifen were the predominating species.read more
Citations
More filters
Journal ArticleDOI
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs : Evidence for a provisional safety margin in drug development
William S. Redfern,Leif Carlsson,A.S Davis,W G Lynch,I MacKenzie,S Palethorpe,Peter K. S. Siegl,I. Strang,A.T Sullivan,Rob Wallis,A. J. Camm,Tim Hammond +11 more
TL;DR: The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use.
Journal ArticleDOI
Pharmacogenetics of Tamoxifen Biotransformation Is Associated With Clinical Outcomes of Efficacy and Hot Flashes
Matthew P. Goetz,James M. Rae,Vera J. Suman,Stephanie L. Safgren,Matthew M. Ames,Daniel W. Visscher,Carol Reynolds,Fergus J. Couch,Wilma L. Lingle,David A. Flockhart,Zeruesenay Desta,Edith A. Perez,James N. Ingle +12 more
TL;DR: In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with the previous observation that CYP3A5*3 variant was not associated with any of these clinical outcomes.
Journal ArticleDOI
Polymorphism of human cytochrome P450 enzymes and its clinical impact
TL;DR: Current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) is highlighted to understand the large interindividual variability in drug clearance and responses in clinical practice and to improve the efficacy and safety of both prospective and currently available drugs.
Journal ArticleDOI
Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6.
TL;DR: Variable activity of these P450s, brought about by genetic polymorphisms and drug interactions, may alter the balance of TAM effects in vivo.
Journal ArticleDOI
Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen
Werner Schroth,Matthew P. Goetz,Ute Hamann,Peter A. Fasching,Peter A. Fasching,Marcus Schmidt,Stefan Winter,Stefan Winter,Peter Fritz,Peter Fritz,W. Simon,Vera J. Suman,Matthew M. Ames,Stephanie L. Safgren,Mary J. Kuffel,Hans Ulrich Ulmer,Julia Boländer,Reiner Strick,Matthias W. Beckmann,Heinz Koelbl,Richard M. Weinshilboum,James N. Ingle,Michel Eichelbaum,Michel Eichelbaum,Matthias Schwab,Matthias Schwab,Hiltrud Brauch,Hiltrud Brauch +27 more
TL;DR: Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP 2D6 alleles was associated with better clinical outcomes and the absence of nonfunctional or reduced-function alleles with worse outcomes.
References
More filters
Journal ArticleDOI
The Attractions of Proteins for Small Molecules and Ions
TL;DR: The number and variety of known compounrjs between proteins and small molecules are increasing rapidly and make a fascinating story as discussed by the authors, and there are many compounds of serum albumin, which was used during the war by many chemists, most of whom found at least one 6ew compound.
Journal ArticleDOI
Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies
TL;DR: The method utilizes the difference between the rate of electrophoretic migration of proteins and of their antibody complexes in agarose gel to perform quantitative analysis of proteins with a charge differing from that of the bulk of the immunoglobulins.
Journal ArticleDOI
The pharmacology and clinical uses of tamoxifen
B. J.A. Furr,Virgil Craig Jordan +1 more
Journal Article
Drug binding to human alpha-1-acid glycoprotein in health and disease.
J M Kremer,J Wilting,L H Janssen +2 more
Journal ArticleDOI
A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity
TL;DR: The potent activity of monohydroxylated (monohydroxytamoxifen) in vivo and in vitro suggests that this compound could be an important new tool for the subcellular investigation of oestrogenic and antioestrogensic events.
Related Papers (5)
CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment
Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
O. Abe,R. Abe,K. Enomoto,K. Kikuchi,H. Koyama,H. Masuda,Y. Nomura,K. Sakai,K. Sugimachi,T. Tominaga,J. Uchino,M. Yoshida,J. L. Haybittle,C Davies,V. J. Harvey,T. M. Holdaway,R. G. Kay,B. H. Mason,John F. Forbes,Nicholas Wilcken,M. Gnant,Raimund Jakesz,M. Ploner,H. M. A. Yosef,C. Focan,J. P. Lobelle,U. Peek,G. D. Oates,Janet T. Powell,M. Durand,L. Mauriac,A. Di Leo,Stella Dolci,M.J. Piccart,M. B. Masood,D. Parker,J. J. Price,Pierre Hupperets,Sue Jackson,Joseph Ragaz,Donna L. Berry,Gloria Broadwater,C. Cirrincione,Hyman B. Muss,Larry Norton,Raymond B. Weiss,H. Abu-Zahra,S. M. Portnoj,Michael J. Baum,Jack Cuzick,Joan Houghton,David Riley,N. H. Gordon,H. L. Davis,A. Beatrice,J. Mihura,A. Naja,Y. Lehingue,P. Romestaing,J. B. Dubois,Thierry Delozier,J. Mace-Lesec'h,P. Rambert,O. Andrysek,J. Barkmanova,Julie Owen,P. Meier,A Howell,G. C. Ribeiro,R. Swindell,R Alison,J Boreham,Matthew Clarke,Rory Collins,Sarah C. Darby,P. Elphinstone,Vaughan Evans,Jon Godwin,Richard Gray,C. S. Harwood,C. Hicks,Spencer L. James,Elizabeth MacKinnon,Paul McGale,Theresa McHugh,Graham M. Mead,Richard Peto,Yisong Wang,J. Albano,C. F. de Oliveira,H. Gervasio,J. Gordilho,H Johansen,Henning T. Mouridsen,Rebecca Gelman,J.R. Harris,I. C. Henderson,Charles L. Shapiro,K. W. Andersen,C. K. Axelsson,M. Blichert-Toft,S. Moller,Jens Overgaard,Marie Overgaard,Carsten Rose,B. Cartensen,T. Palshof,H. J. Trampisch,Otilia Dalesio,E.G.E. de Vries,Sjoerd Rodenhuis,H. van Tinteren,R. L. Comis,Nancy E. Davidson,Nicholas J. Robert,George W. Sledge,Douglass C. Tormey,William C. Wood,David Cameron,Udi Chetty,P. Forrest,W. Jack,J. Rossbach,Jan G. M. Klijn,A. D. Treurniet-Donker,W. L. J. van Putten,Alberto Costa,Umberto Veronesi,H. Bartelink,L. Duchateau,C. Legrand,RJ Sylvester,J.A. van der Hage,C.J.H. van de Velde,M. P. Cunningham,R. Catalano,R. H. Creech,Jacques Bonneterre,P. Fargeot,Pierre Fumoleau,Pierre Kerbrat,Moïse Namer,Walter Jonat,Manfred Kaufmann,Martin Schumacher,G. von Minckwitz,G. Bastert,H. Rauschecker,R. Sauer,Willi Sauerbrei,A.J. Schauer,A. de Schryver,L. Vakaet,M. Belfiglio,A. Nicolucci,F. Pellegrini,M. Sacco,M. Valentini,C. S. McArdle,D. C. Smith,E. Galligioni,Francesco Boccardo,AU Rubagotti,D. M. Dent,C. A. Gudgeon,A. Hacking,A. Erazo,J. Y. Medina,M. Izuo,Y. Morishita,H. Takei,I.S. Fentiman,John L. Hayward,R D Rubens,D. Skilton,H. Graeff,Fritz Jänicke,C. Meisner,H. R. Scheurlen,D. von Fournier,Urania Dafni,G. Fountzilas,P. Klefstrom,Carl Blomqvist,T. Saarto,R. Margreiter,Bernard Asselain,R. J. Salmon,J. R. Vilcoq,Rodrigo Arriagada,Christopher Hill,A. Laplanche,M. G. Le,M. Spielmann,Paolo Bruzzi,E. Montanaro,R. Rosso,M. R. Sertoli,M. Venturini,Dino Amadori,J. Benraadt,M. Kooi,A. O. van de Velde,J. A. van Dongen,J. B. Vermorken,Monica Castiglione,F. Cavalli,A. S. Coates,J. Collins,JF Forbes,Richard D. Gelber,A. Goldhirsch,J. Lindtner,Karen N. Price,C. M. Rudenstam,H.-J. Senn,Judith M Bliss,Clair Chilvers,R. C. Coombes,Emma Hall,Michel Marty,R. V. Borovik,G. Brufman,H. Hayat,E. Robinson,N. Wigler,Gianni Bonadonna,T. Camerini,G. De Palo,M. Del Vecchio,F. Formelli,Pinuccia Valagussa,A Martoni,F. Pannuti,G. Cocconi,A. Colozza,R. Camisa,K. Aogi,S. Takashima,T. Ikeda,K. Inokuchi,K. Sawa,H. Sonoo,S. Korzeniowski,J. Skolyszewski,M. Ogawa,J. Yamashita,J. Bonte,R. Christiaens,Robert Paridaens,W. Van den Boegart,P. Martin,S. Romain,T. Hakes,Clifford A. Hudis,R. Wittes,G. Giokas,D. Kondylis,B. Lissaios,R. de la Huerta,M. G. Sainz,R. Altemus,K. Cowan,David N. Danforth,Allen S. Lichter,Marc E. Lippman,Joyce A. O'Shaughnessy,Lori J. Pierce,Seth M. Steinberg,D. Venzon,JoAnne Zujewski,A. Paradiso,M. De Lena,F. Schittulli,J. Myles,J. L. Pater,Kathleen I. Pritchard,Stewart J. Anderson,G. Bass,Anna Brown,John Bryant,J. Costantino,James J. Dignam,Bernard Fisher,C Redmond,Sam Wieand,Norman Wolmark,I. M. Jackson,Mike K. Palmer,JN Ingle,Vera J. Suman,Nils-Olof Bengtsson,H. Jonsson,Lars-Gunnar Larsson,J. P. Lythgoe,M. Kissin,Bjørn Erikstein,E Hannisdal,A. B. Jacobsen,J. E. Varhaug,S. Gundersen,Martin Hauer-Jensen,H. Host,R. Nissen-Meyer,Roger W. Blamey,A. Mitchell,Morgan Da,J.F.R. Robertson,M. Di Palma,G. Mathe,J. L. Misset,R. M. Clark,Mitch Levine,K Morimoto,Y. Takatsuka,E. Crossley,Al Harris,Denis Talbot,Mark Taylor,B. di Blasio,V. Ivanov,Vladimir Semiglazov,J. Brockschmidt,M. R. Cooper,H. Ueo,Carla I. Falkson,Roger A'Hern,Stanley W. Ashley,T. J. Powles,Ian E. Smith,John Yarnold,J.-C. Gazet,N. Cocoran,N. Deshpande,L. di Martino,P. Douglas,A. Lindtner,G Notter,A. J. S. Bryant,G. H. Ewing,L. A. Firth,J. L. Krushen-Kosloski,L. Foster,W.D. George,Helen J. Stewart,P. Stroner,Per-Uno Malmström,Torgil Möller,Stefan Rydén,Ingrid Tengrup,Lena Tennvall-Nittby,J. Carstenssen,M. Dufmats,Thomas Hatschek,Bo Nordenskjöld,Martin Söderberg,John T. Carpenter,KS Albain,J. Crowley,Stuart A. Green,Silvana Martino,CK Osborne,Peter M. Ravdin,U. Glas,Ulla Johansson,L E Rutqvist,T. Singnomklao,Arne Wallgren,Rudolf Maibach,Beat Thürlimann,Hermann Brenner,A. Hercbergs,M Yoshimoto,Gerrit DeBoer,Alexander H.G. Paterson,JW Meakin,T. Panzarella,Y. Shan,Y. F. Shao,X. Wang,D. B. Zhao,Z. M. Chen,H. C. Pan,J. Bahi,M. Reid,M. Spittle,G. P. Deutsch,F. Senanayake,D. L. W. Kwong,Angelo Raffaele Bianco,Chiara Carlomagno,M. De Laurentiis,S. De Placido,Aman U. Buzdar,Tae C Smith,Jonas Bergh,Lars Holmberg,Göran Liljegren,Jan Nilsson,M. Seifert,P. Sevelda,C. C. Zielinsky,R. B. Buchanan,M. Cross,G.T. Royle,Janet A. Dunn,Robert Kerrin Hills,Michael Lee,J. M. Morrison,D. Spooner,A. Litton,Rowan T. Chlebowski,H. Caffier +412 more