Date of Graduation
School of Pharmacy
Timothy S. Tracy.
Studies have shown that CYP2C9.1 mediated metabolism of flurbiprofen and naproxen is activated by dapsone. However, dapsone activation has not been studied in the allelic variant forms of CYP2C9. Six concentrations of flurbiprofen or naproxen were co-incubated with six concentrations of dapsone and with reconstituted, purified CYP2C9.1, CYP2C9.2 (R144C), CYP2C9.3 (1359L), or CYP2C9.5 (D360E), in order to assess degrees of activation. Dapsone increased the efficiency (Vmax/Km) of flurbiprofen metabolism 690%, 3029%, 4600%, and 2100% by CYP2C9.1, CYP2C9.2, CYP2C9.3, and CYP2C9.5, respectively. Dapsone increased the efficiency of naproxen metabolism 591%, 1400%, 1150%, and 2100%, by CYP2C9.1, CYP2C9.2, CYP2C9.3, and CYP2C9.5, respectively. Also, dapsone normalized the kinetic profile of naproxen from biphasic (CYP2C9.1 and CYP2C9.2) or linear (CYP2C9.3 and CYP2C9.5) to hyperbolic for all variant forms. The amino acid substitutions of CYP2C9 allelic variants appear to affect the degree of dapsone activation.
Hummel, Matthew Aaron, "Dapsone activation of CYP2C9 allelic variants" (2003). Graduate Theses, Dissertations, and Problem Reports. 1737.