Arylamine N-acetyltransferase acetylation polymorphisms: paradigm for pharmacogenomic-guided therapy- a focused review

ABSTRACT

Introduction

The N-acetylation polymorphism has been the subject of comprehensive reviews describing the role of arylamine N-acetyltransferase 2 (NAT2) in the metabolism of numerous aromatic amine and hydrazine drugs.

Areas covered

We describe and review data that more clearly defines the effects of NAT2 haplotypes and genotypes on the expression of acetylator phenotype towards selected drugs within human hepatocytes in vitro, within human hepatocyte cultures in situ, and clinical measures such as bioavailability, plasma metabolic ratios of parent to N-acetyl metabolite, elimination rate constants and plasma half-life, and/or clearance determinations in human subjects. We review several drugs (isoniazid, hydralazine, sulfamethazine, amifampridine, procainamide, sulfasalazine, amonafide and metamizole) for which NAT2 phenotype-guided therapy may be important. The value of pharmacogenomics-guided isoniazid therapy for the prevention and treatment of tuberculosis is presented as a paradigm for NAT2 phenotype-dependent dosing strategies.

Expert opinion

Studies in human subjects and cryopreserved human hepatocytes show evidence for rapid, intermediate and slow acetylator phenotypes, with further data suggesting genetic heterogeneity within the slow acetylator phenotype. Incorporation of more robust NAT2 genotype/phenotypes relationships, including genetic heterogeneity within the slow acetylator phenotype, should lead to further advancements in both health outcomes and cost benefit for prevention and treatment of tuberculosis.

KEYWORDS:

• Acetylation polymorphism
• isoniazid
• N-acetyltransferase 2
• pharmacogenomic-guided therapy
• tuberculosis

Article highlights

• The effects of the N-acetylation polymorphism on metabolism, efficacy, and/or toxicity of numerous drugs is described, including:

  • isoniazid

  • hydralazine

  • sulfamethazine

  • amifampridine

  • procainamide

  • sulfasalazine

  • amonafide

  • metamizole

• Studies in human subjects and cryopreserved human hepatocytes show evidence for rapid, intermediate and slow acetylator phenotypes, with further data suggesting genetic heterogeneity within the slow acetylator phenotype.

• The current COVID-19 pandemic is exacerbating effects of tuberculosis in many countries.

• Point of care testing for NAT2 phenotype/genotype and providing dose guidance could improve safety and efficacy of isoniazid for tuberculosis prevention and treatment.

• More robust methods for assessing N-acetylation genotype and/or phenotype should lead to further advancements in health outcomes and cost benefits.

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 funded by The National Institute of Health [grant number: P30-ES030283; T32-ES011564].