Abstract
Drugs are serious but underestimated causative agents of interstitial lung disease (ILD). Both cytotoxic and immune mechanisms may be involved in drug-induced ILD (DI-ILD). We aimed to investigate whether polymorphisms of relevant CYP enzymes involved in the metabolization of tamsulosin might explain the pathologic mechanism of the DI-ILD in the cases with suspected tamsulosin DI-ILD. We collected 22 tamsulosin-associated DI-ILD cases at two ILD Expertise Centers in the Netherlands between 2009 and 2020. CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 single nucleotide polymorphisms were genotyped and compared with a control group of 78 healthy Caucasian male volunteers. Nine cases were phenotyped as CYP2D6 poor metabolizers and 13 as CYP2D6 intermediate metabolizers. The phenotypes of the cases differed significantly from those of the healthy controls, with more poor metabolizers. After withdrawal of tamsulosin, the pulmonary condition of three cases had improved, six patients had stabilized, and one patient stabilized after reducing the tamsulosin dose. The described 22 cases suggest that an association between the presence of CYP2D6 allelic variants and tamsulosin-associated ILD is highly likely. These cases highlight the importance of both clinical and genetic risk stratification aimed to achieve a more accurate prevention of DI-ILD in the future and enhance the quality of life of patients.
Highlights
Nowadays, it is well recognized that genetic polymorphisms in genes coding for enzymes responsible for drug metabolism and drug disposition are of great importance for the efficacy and toxicity of medicines [1]
Of the remaining 12 cases, six had died of comorbidities and three had died of respiratory failure, and of three cases follow-up data were lacking
Tamsulosin has so far not been recognized in general clinical practice as an agent that might be associated with the development and/or progression of lung damage
Summary
It is well recognized that genetic polymorphisms in genes coding for enzymes responsible for drug metabolism and drug disposition are of great importance for the efficacy and toxicity of medicines [1]. It is generally agreed that the cytochrome P450 (CYP) superfamily of enzymes, with more than 1000 isoenzymes, five of which (CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2) metabolize 90% of all drugs, contributes greatly to the metabolization of drugs in the human body. Identifying polymorphisms of these CYPs is mostly done to predict or explain drug target serum levels, e.g., a reduced CYP metabolism leads to increased serum drug levels and to increased toxicity.
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