Lung as reservoir for antidepressants in pharmacokinetic drug interactions

doi:10.1016/S0140-6736(97)07336-4

The Lancet

Volume 351, Issue 9099, 31 January 1998, Pages 332-335

https://doi.org/10.1016/S0140-6736(97)07336-4 Get rights and content

Summary

Background

Although high-affinity imipramine binding sites have been reported in both rat and human lung, the role of the lungs in the pharmacokinetics of antidepressants has not received much attention. Substantial accumulation of selective serotonin-reuptake inhibitors (SSRIs) in the lungs has been reported. We have investigated the role of the lungs in pharmacokinetic drug interactions between tricyclic antidepressants and SSRIs.

Methods

We used a carbon-11-labelled form of the imipramine derivative cyanoimipramine to measure uptake in the lungs and brain of healthy volunteers by positron emission tomography. Clomipramine (50 mg) was administered to measure the effect of antidepressants with high affinity for the serotonin transporter on lung and brain uptake.

Findings

A large proportion of the injected ¹¹C-cyanoimipramine (68–86% in the four volunteers) was extracted by the lungs. Clomipramine decreased the lung uptake from 68% to 35% and from 81% to 54% in the two volunteers studied. By contrast, whole-brain uptake was low in control studies (1·7–2·0% in three volunteers) and increased after clomipramine administration (to 4·5–4·9%). Plasma radioactivity was also higher after clomipramine than in control studies.

Interpretation

The lungs may function as a reservoir for antidepressants with high affinity to the serotonin transporter. The accumulated antidepressants may be displaced by other antidepressants, and this displacement would substantially increase plasma concentrations and thus cause toxic effects.

Introduction

High-affinity imipramine binding sites¹ and accumulation of imipramine in the lungs² have been found in several mammalian species, including human beings.³ However, the pharmacokinetics and drug interactions of antidepressants have been investigated mainly in relation to drug metabolism in the liver, and the role of the lungs has received little attention. There is an interaction between tricyclic antidepressants and selective serotonin-reuptake inhibitors (SSRIs); plasma concentrations of tricyclic antidepressants increased when SSRIs were added to stable tricyclic-antidepressant dosing regimens.⁴ Inhibition of P450 enzymes by SSRIs is a likely mechanism. However, SSRIs such as fluoxetine accumulate in the lungs,5, 6 which may be another site of interaction between fluoxetine and tricyclic antidepressants.⁷ Junod⁸ warned of the possibility that accumulated imipramine could be released from the lungs by administration of another drug with similar characteristics. The characteristics of the imipramine binding site in the lungs must be clarified so that a better understanding of the pharmacokinetic mechanism of antidepressants can be obtained and the risk of the combination therapy with antidepressants reduced.

We have labelled the imipramine derivative cyanoimipramine with carbon-11 for study by positron tomography (PET). Cyanoimipramine binds with high affinity to imipramine binding sites.⁹ Our aim in this study was to investigate the role of the lungs in the pharmacokinetic drug interactions of antidepressants in healthy volunteers. We used ¹¹C-cyanoimipramine and a pharmacological dose of clomipramine (Anafranil, Ciba-Geigy Japan Ltd, Takarazuka, Japan). This tricyclic antidepressant is also a potent inhibitor of serotonin reuptake, and is the only such drug available in Japan.

Section snippets

Volunteers

Seven healthy men, aged 20–22 years, with no history of problems related to drugs or alcohol, were recruited from universities. None had a relevant medical history. The study was approved by the ethics and radiation safety committees of the National Institute of Radiological Sciences. Written informed consent was obtained from each volunteer. Four volunteers took part in the lung-uptake study (and two of these were also studied after administration of clomipramine); three volunteers took part

Results

There was a substantial uptake of ¹¹C-cyanoimipramine in the lung, and this accumulation was blocked by pretreatment with clomipramine (figure 1).

In control studies in four volunteers, the extraction of ¹¹C-cyanoimipramine by the lung was 68–86% within the first 90 s (table). The time course of lung uptake showed a biphasic decline, with an initial rapid phase and subsequent slow phase, remaining high throughout the PET run (figure 2, upper panel). 40 min after the tracer injection, 76–94% of

Discussion

We have shown high uptake of ¹¹C-cyanoimipramine in the lungs, which was blocked by clomipramine and followed by an increase in plasma and brain radioactivity. These results suggest a common binding site for ¹¹C-cyanoimipramine and clomipramine in the lungs. The inhibition of tritium-labelled imipramine binding in rat lung is stereoselective.¹ IC₅₀ values suggest that ³H-imipramine binding is identical in lung and brain cortex.¹ Serotonin transporter is expressed on human pulmonary membranes.¹¹

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Early ReportLung as reservoir for antidepressants in pharmacokinetic drug interactions

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Volunteers

Results

Discussion

Eur J Pharmacol

Biochem Biophys Res Commun

Nucl Med Biol

Nucl Med Biol

Life Sci

Accumulation of 14C-imipramine in isolated perfused rat lungs

J Pharmacol Exp Ther

Selective serotonin reuptake inhibitors and tricyclic antidepressants in combination: interaction and therapeutic uses

Br J Psychiatry

Fluoxetine: clinical pharmacology and physiologic disposition

J Clin Psychiatry

Effect of fluoxetine on metabolism of tricyclic antidepressants in the lungs

Am J Psychiatry

Early Report
Lung as reservoir for antidepressants in pharmacokinetic drug interactions

Accumulation of ¹⁴C-imipramine in isolated perfused rat lungs