Cytochrome Oxidase 2D6 Gene Polymorphism in Primary Open-Angle Glaucoma With Various Effects to Ophthalmic Timolol

Abstract

Timolol is used topically for the treatment of glaucoma and metabolized by cytochrome P450 (CYP) 2D6 in the liver. The aim of this study is to test the hypothesis that CYP 2D6 single-nucleotide polymorphism (SNP) is associated with drug effects of ophthalmic timolol. A total of 133 primary open-angle glaucoma (POAG) subjects underwent the ophthalmic single timolol administration and the drug effects were observed, including lowering the effects of intraocular pressure (IOP) and side effects (i.e., appearing bradycardia). Eight SNPs of CYP2D6 were investigated in 73 subjects by a SNPstream genotyping system. The relationship between the effects of timolol and CYP2D6 Arg296Cys and Ser486Thr genotype distribution in these POAG subjects was analyzed. Topical timolol administration had significant effect on IOP (P = 0.000) and heart rate (HR) (P = 0.000) in all 133 subjects, and individual ocular hypotensive effect of timolol varied between 0 and 23 mmHg. Individual effect of HR varied between -31 and 10 beats per minute, in the present study. According to SNP genotyping in 73 subjects, there was no significant difference of IOP between subjects with different CYP2D6 Arg296Cys (P = 0.308) or Ser486Thr genotypes (P = 0.741). The effect of timolol on HR was significantly different between subjects with different Arg296Cys genotypes (P = 0.046). Timolol-induced bradycardia tended to occur in subjects with Arg296Cys CT and TT genotype when compared with CC genotype (P = 0.009). CYP2D6 SNP Arg296Cys appeared to be correlative with the intersubject variability seen with timolol in POAG subjects. Subjects with CC genotype trended to avoid timolol-induced bradycardia, and subjects with TT genotype trended to have poorer timolol-induced ocular hypotensive effects.