Analysis of the mechanism of prolonged persistence of drug interaction between terbinafine and amitriptyline or nortriptyline

Akiko Mikami, Satoko Hori, Hisakazu Ohtani, Yasufumi Sawada

Research output: Contribution to journalArticle

Abstract

The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA-metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound Ki values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug�drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound Ki values of 13.7 and 12.4nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency.

Original languageEnglish
Pages (from-to)1010-1020
Number of pages11
JournalBiological and Pharmaceutical Bulletin
Volume40
Issue number7
DOIs
Publication statusPublished - 2017

Fingerprint

terbinafine
Nortriptyline
Amitriptyline
Drug Interactions
Tricyclic Antidepressive Agents
Cytochrome P-450 CYP2D6
Area Under Curve
Pharmacokinetics

Keywords

  • Amitriptyline
  • CYP2D6
  • Drug interaction
  • Nortriptyline
  • Terbinafine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Analysis of the mechanism of prolonged persistence of drug interaction between terbinafine and amitriptyline or nortriptyline. / Mikami, Akiko; Hori, Satoko; Ohtani, Hisakazu; Sawada, Yasufumi.

In: Biological and Pharmaceutical Bulletin, Vol. 40, No. 7, 2017, p. 1010-1020.

Research output: Contribution to journalArticle

@article{d6cf135e690f43be8f3fd6698170557b,
title = "Analysis of the mechanism of prolonged persistence of drug interaction between terbinafine and amitriptyline or nortriptyline",
abstract = "The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA-metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound Ki values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug�drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound Ki values of 13.7 and 12.4nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency.",
keywords = "Amitriptyline, CYP2D6, Drug interaction, Nortriptyline, Terbinafine",
author = "Akiko Mikami and Satoko Hori and Hisakazu Ohtani and Yasufumi Sawada",
year = "2017",
doi = "10.1248/bpb.b16-01004",
language = "English",
volume = "40",
pages = "1010--1020",
journal = "Biological and Pharmaceutical Bulletin",
issn = "0918-6158",
publisher = "Pharmaceutical Society of Japan",
number = "7",

}

TY - JOUR

T1 - Analysis of the mechanism of prolonged persistence of drug interaction between terbinafine and amitriptyline or nortriptyline

AU - Mikami, Akiko

AU - Hori, Satoko

AU - Ohtani, Hisakazu

AU - Sawada, Yasufumi

PY - 2017

Y1 - 2017

N2 - The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA-metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound Ki values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug�drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound Ki values of 13.7 and 12.4nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency.

AB - The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA-metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound Ki values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug�drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound Ki values of 13.7 and 12.4nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency.

KW - Amitriptyline

KW - CYP2D6

KW - Drug interaction

KW - Nortriptyline

KW - Terbinafine

UR - http://www.scopus.com/inward/record.url?scp=85021657362&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021657362&partnerID=8YFLogxK

U2 - 10.1248/bpb.b16-01004

DO - 10.1248/bpb.b16-01004

M3 - Article

VL - 40

SP - 1010

EP - 1020

JO - Biological and Pharmaceutical Bulletin

JF - Biological and Pharmaceutical Bulletin

SN - 0918-6158

IS - 7

ER -