{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T17:15:52Z","timestamp":1770743752215,"version":"3.49.0"},"reference-count":31,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2012,3,12]],"date-time":"2012-03-12T00:00:00Z","timestamp":1331510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2012,4]]},"abstract":"<jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003A single nucleotide polymorphism in <jats:italic>ABCB1<\/jats:italic>, which encodes P\u2010glycoprotein, has retrospectively been associated with symptoms of nortriptyline\u2010induced postural hypotension in depressed patients.<\/jats:p><jats:p>\u2022\u2003This finding needs to be replicated in independent studies before recommendations regarding pharmacogenetic testing can be made.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003In a prospective study of healthy volunteers homozygous for <jats:italic>ABCB1<\/jats:italic> (1236\u20102677\u20103435, TTT\/TTT or CGC\/CGC), a single dose of nortriptyline was administered, plasma exposure was determined and blood pressure and heart rate were monitored during posture change.<\/jats:p><jats:p>\u2022\u2003No differences between <jats:italic>ABCB1<\/jats:italic> haplotype groups were found in plasma exposure of nortriptyline and its active metabolites, E\u2010 and Z\u201010\u2010hydroxynortriptyline. The heart rate response to posture change was increased with nortriptyline, whereas there was no difference in blood pressure response. However, no differences between haplotype groups were observed except that the pre dose heart rate response to standing was greater in the TTT than CGC homozygotes.<\/jats:p><jats:p>\u2022\u2003The association between <jats:italic>ABCB1<\/jats:italic> polymorphisms and nortriptyline\u2010induced postural hypotension found in a previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.<\/jats:p><jats:p><jats:bold>AIMS<\/jats:bold> To investigate the influence of <jats:italic>ABCB1<\/jats:italic> (1236\u20102677\u20103435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline\u2010induced postural hypotension in healthy volunteers.<\/jats:p><jats:p><jats:bold>METHODS<\/jats:bold> Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of <jats:italic>ABCB1<\/jats:italic> (1236\u20102677\u20103435), who were administered a single dose of nortriptyline 25\u2003mg. Plasma exposure of nortriptyline and its active metabolites, E\u2010 and Z\u201010\u2010hydroxynortriptyline, was determined over 72\u2003h. Heart rate and blood pressure responses to posture change (active standing and passive head\u2010up tilt) were measured continuously using finger plethysmography.<\/jats:p><jats:p><jats:bold>RESULTS<\/jats:bold> There were no differences in plasma exposure between <jats:italic>ABCB1<\/jats:italic> haplotype groups, as the geometric mean (95% CI) AUC(0,72\u2003h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E\u2010 and Z\u201010\u2010hydroxynortriptyline, respectively. The pre dose heart rate response to standing was greater in the TTT than CGC homozygotes (mean (95% CI) difference 7.4 (1.5, 13.4) beats\u2003min<jats:sup>\u20131<\/jats:sup>, <jats:italic>P<\/jats:italic>\u2003=\u20030.02). At <jats:italic>t<\/jats:italic><jats:sub>max<\/jats:sub> at 8\u2003h post dose, nortriptyline increased the heart rate response to posture change in all subjects with mean (95% CI) \u0394 heart rate values of 7.4 (3.6, 11.3) beats\u2003min<jats:sup>\u20131<\/jats:sup> on active standing (<jats:italic>P<\/jats:italic>\u2003=\u20030.0009) and 4.8 (2.0, 7.6) beats\u2003min<jats:sup>\u20131<\/jats:sup> on head\u2010up tilt (<jats:italic>P<\/jats:italic>\u2003=\u20030.002), but no difference was observed between haplotype groups. There was no difference in blood pressure response to posture change in either group.<\/jats:p><jats:p><jats:bold>CONCLUSION<\/jats:bold> The association between <jats:italic>ABCB1<\/jats:italic> polymorphisms and nortriptyline\u2010induced postural hypotension found in the previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.<\/jats:p>","DOI":"10.1111\/j.1365-2125.2011.04126.x","type":"journal-article","created":{"date-parts":[[2011,10,14]],"date-time":"2011-10-14T13:37:30Z","timestamp":1318599450000},"page":"619-628","source":"Crossref","is-referenced-by-count":14,"title":["Influence of <i>ABCB1<\/i> (P\u2010glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline\u2010induced postural hypotension in healthy volunteers"],"prefix":"10.1111","volume":"73","author":[{"given":"Berit Packert","family":"Jensen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca 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