An update on drug interaction considerations in the therapeutic use of carbonic anhydrase inhibitors

ABSTRACT

Introduction: Carbonic anhydrase inhibitors (CAIs) have been in clinical use for decades for the management of various disorders. An update on their drug–drug interactions is presented here considering these main therapeutic areas and drugs: glaucoma (acetazolamide, methazolamide, dichlorophenamide, dorzolamide, and brinzolamide); epilepsy/obesity (sulthiame, topiramate, and zonisamide); arthritis/inflammation (celecoxib and polmacoxib) and hypoxic tumors (SLC-0111).

Areas covered: Drug interactions reported between CAIs with various other pharmacological agents are reviewed in publications after 2016, when the previous review was published. Most reported interactions concern the antiepileptics sulthiame, topiramate, and zonisamide, as they are part of complex regimens in which drugs controlling this disorder are administered. Fewer interactions were reported for the anti-glaucoma agents, whereas synergistic combinations of celecoxib with antibiotics or SLC-0111 with various antitumor drugs were extensively investigated.

Expert opinion: Drug interactions involving CAIs may be used both for monitoring the clinical efficacy of these agents when co-administered with other drugs but also for better controlling some diseases, such as hypoxic tumors, case for which the combination of CAIs with other anticancer agents (histone deacetylase inhibitors, alkylating agents, antimetabolite nucleosides, angiogenesis inhibitors, and immune checkpoint inhibitors) proved to be synergistic.

KEYWORDS:

• Acetazolamide
• carbonic anhydrase
• brinzolamide
• celecoxib
• dorzolamide
• inhibitor
• methazolamide
• sultiame
• SLC-0111
• topiramate
• zonisamide

Article Highlights

• Carbonic anhydrase (CA) catalyzes the reversible hydration of CO₂ to bicarbonate and protons.

• CA inhibitors (CAIs) in clinical use belong to the sulfonamide and sulfamate classes, and act as diuretics, antiglaucoma, antiepileptic, antiobesity, and anti-high altitude disease agents.

• Anticancer agents, both small molecule and monoclonal antibodies, belonging to the CAIs are in clinical development.

• Most drug–drug interaction for this class of pharmacological agents was reported for the antiepileptic agents topiramate and zonisamide.

• Risks of developing toxicity and serious side effects should be considered when antiepileptic CAIs such as topiramate and zonisamide are used in combination with other AEDs, e.g. clobazam, cannabidiol, barbiturates, etc.

• Topiramate efficacy is reduced by the concomitant administration of caffeine, and the drug affects the plasma concentrations of non-vitamin K oral coagulants of the serine protease inhibitor type.

• Celecoxib is synergistic with β-lactam antibiotics for the management of drug-resistant bacteria.

• There are many synergistic effects between antitumor CAIs such as SLC-0111 and HDAC inhibitors, alkylating agents, antimetabolite nucleosides, angiogenesis inhibitors, and immune checkpoint inhibitors.

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.