Antituberculosis Chemotherapy

Editor(s): Donald P.R. (Tygerberg) 
van Helden P.D. (Tygerberg) 
Table of Contents
Vol. 40, 2011
Section title: The Future

Chapter 18: Pharmacogenetics of Antituberculosis Drugs

Aarnoutse R.
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Pharmacogenetics can be defined as the study of genetic factors affecting (desirable or undesirable) drug responses. The genetic polymorphism in the acetylation of isoniazid was one of the earliest described pharmacogenetic traits. Trimodality in isoniazid elimination has been demonstrated, resulting in homozygous fast, heterozygous fast (or intermediate) and slow metabolizers. This ‘acetylator status’ can be assessed by phenotyping or genotyping. Exposure to isoniazid is considerably lower in homozygous fast than in intermediate or slow acetylators, but the acetylator status is only relevant with highly intermittent once weekly isoniazid-containing regimens, with fast acetylators performing less well than slow acetylators. The majority of genotyping studies suggest that slow acetylation and genetic polymorphisms in CYP2E1 and glutathione S-transferase are associated with an increased risk for isoniazid-induced hepatotoxicity, caused by hepatotoxic metabolites. Few studies have addressed the pharmacogenetics of other antituberculosis (anti-TB) drugs. The interindividual variability in exposure to rifampicin is clinically relevant and can be explained to a large extent by polymorphism in genes for organic anion-transporting polypeptides. Clinical application of pharmacogenetics in TB treatment is still in its infancy and warrants more clinical studies, evaluation of cost-effectiveness and overcoming of hurdles associated with implementation of this new approach in clinical practice.

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