Role of the N-acetylation polymorphism in solithromycin metabolism. (June 2017)

• Record Type: Journal Article
• Authors: Hein, David W; Doll, Mark A
• Is Part Of: Pharmacogenomics. Volume 18:Number 8(2017)
• Page Start: 765
• Page End: 772
• Publication Date: 2017-06
• Subjects: acetylation polymorphism -- cryopreserved human hepatocytes -- N-acetyltransferase 2 -- solithromycin; Pharmacogenomics -- Periodicals; 615.1
• DOI: 10.2217/pgs-2017-0045
• Languages: English
• ISSNs: 1462-2416

Abstract

Aim: Solithromycin is a new macrolide antibiotic for the potential treatment of bacterial pneumonia.Materials & methods: Solithromycin N -acetylation by human NAT1 and NAT2 was investigated following recombinant expression in yeast and in cryopreserved human hepatocytes from rapid, intermediate and slow acetylators.Results: Solithromycin exhibited over twofold higher affinity for recombinant human NAT2 than NAT1. Apparent maximum velocities for the N -acetylation of solithromycin catalyzed by the NAT2 allozyme associated with rapid acetylators were significantly (p < 0.01) higher than by the NAT2 allozymes associated with slow acetylators. Robust gene dose responses (rapid>intermediate>slow acetylators) were exhibited in cryopreserved human hepatocytes in situ following incubation with 100 μM solithromycin.Conclusion: Solithromycin is N -acetylated by human NAT1 and NAT2 and the role of the NAT2 acetylation polymorphism on solithromycin metabolism may be concentration dependent.