Influence of ABCB1 (P‐glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers

Abstract

A single nucleotide polymorphism in ABCB1, which encodes P-glycoprotein, has retrospectively been associated with symptoms of nortriptyline-induced postural hypotension in depressed patients. This finding needs to be replicated in independent studies before recommendations regarding pharmacogenetic testing can be made. In a prospective study of healthy volunteers homozygous for ABCB1 (1236-2677-3435, 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. No differences between ABCB1 haplotype groups were found in plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline. 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. The association between ABCB1 polymorphisms and nortriptyline-induced 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. AIMS To investigate the influence of ABCB1 (1236-2677-3435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers. Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of ABCB1 (1236-2677-3435), who were administered a single dose of nortriptyline 25 mg. Plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline, was determined over 72 h. Heart rate and blood pressure responses to posture change (active standing and passive head-up tilt) were measured continuously using finger plethysmography. There were no differences in plasma exposure between ABCB1 haplotype groups, as the geometric mean (95% CI) AUC(0,72 h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E- and Z-10-hydroxynortriptyline, 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 min(-1) , P = 0.02). At t(max) at 8 h post dose, nortriptyline increased the heart rate response to posture change in all subjects with mean (95% CI) Δ heart rate values of 7.4 (3.6, 11.3) beats min(-1) on active standing (P = 0.0009) and 4.8 (2.0, 7.6) beats min(-1) on head-up tilt (P = 0.002), but no difference was observed between haplotype groups. There was no difference in blood pressure response to posture change in either group. The association between ABCB1 polymorphisms and nortriptyline-induced 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.