Bupropion Modulation of Dextromethorphan Metabolism

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Solution Overview

Problem

Dextromethorphan has limited systemic exposure in extensive metabolizers due to rapid hepatic metabolism, limiting its clinical utility as a single agent for treating neurological disorders and cough.

Innovation Solution

Co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion with dextromethorphan to inhibit its metabolism, increasing plasma levels and extending its metabolic lifetime, thereby improving therapeutic efficacy and reducing adverse events.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If dextromethorphan is administered alone, then it can treat cough and neurological disorders, but its plasma levels are too low in extensive metabolizers due to rapid hepatic metabolism

Engineering Contradiction:

Improvedextromethorphan plasma levelsVSAvoidtherapeutic efficacy

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent introduces bupropion and its metabolites (hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion) as intermediary substances that modulate dextromethorphan metabolism. These compounds act as mediators by interacting with CYP2D6 enzyme, thereby controlling the metabolic rate of dextromethorphan and achieving therapeutic plasma levels in extensive metabolizers.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the metabolic parameter of dextromethorphan by co-administering bupropion compounds that inhibit CYP2D6 enzyme activity. This parameter change (reducing metabolic rate) transforms extensive metabolizers into functional poor metabolizers, allowing sustained plasma levels of dextromethorphan without increasing the dose.

Inventive Principle:

Principle #35Parameter changes

2Quantity of substance

If dextromethorphan is administered at higher doses to achieve therapeutic levels, then plasma levels increase, but adverse events increase

Engineering Contradiction:

Improvedextromethorphan plasma levelsVSAvoidadverse events

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

Bupropion and its metabolites serve as intermediary substances that selectively inhibit dextromethorphan metabolism without causing significant adverse effects themselves. This intermediary approach allows achieving therapeutic dextromethorphan levels through metabolic modulation rather than direct dose escalation, thereby avoiding dose-proportional adverse events.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent converts the harmful rapid metabolism (which causes low plasma levels) into a beneficial controlled metabolism. By using bupropion compounds to modulate CYP2D6 activity, the previously harmful fast metabolism is transformed into a controlled process that maintains therapeutic levels while minimizing adverse events.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Duration of action of moving object

If dextromethorphan is dosed frequently to maintain plasma levels, then therapeutic coverage is improved, but compliance and convenience deteriorate

Engineering Contradiction:

Improvemetabolic lifetime of dextromethorphanVSAvoiddosing frequency

Core Design Contradiction:

Duration of action of moving objectVSEase of operation

Solution Approach 1:

The patent achieves continuous therapeutic action of dextromethorphan by co-administering bupropion compounds that sustain plasma levels between doses. This continuous metabolic modulation allows less frequent dosing while maintaining therapeutic coverage, improving patient compliance and convenience.

Inventive Principle:

Principle #20Continuity of useful action

Solution Approach 2:

Bupropion and its metabolites are administered preliminarily or concurrently with dextromethorphan to pre-modulate the metabolic pathway. This preliminary action ensures that when dextromethorphan is administered, its metabolism is already controlled, extending its effective duration and reducing the need for frequent redosing.

Inventive Principle:

Principle #10Preliminary action

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The co-administration of these compounds significantly increases dextromethorphan plasma levels, allowing for less frequent dosing without loss of efficacy, enhances therapeutic properties, and reduces adverse effects, particularly in extensive metabolizers.

Implementation Method 1

Co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion with dextromethorphan to inhibit its metabolism

Methodology Applied

Scientific EffectMetabolic inhibition: Enzyme

Data Source

PatentUS11590124B2Bupropion as a modulator of drug activity

Publication Date: 2023.02.28 ANTECIP BIOVENTURES II LLC

AI summary

Dosage forms, drug delivery systems, and methods related to sustained release of dextromethorphan or improved therapeutic effects are disclosed. Typically, bupropion or a related compound is orally administered to a human being to be treated with, or being treated with, dextromethorphan.