Inhibition of the Rat Cytochrome P450 3A2 by an Antisense Phosphorothioate Oligodeoxynucleotide In Vivo

CYP3A2 is one of the most abundantly expressed cytochrome P450s (CYPs) in the rat liver and metabolizes numerous clini-cally important drugs. Studies were designed to examine effi-cacy, potency and specificity of antisense inhibition of CYP3A2 in vivo. Three phosphorothioate ODNs were used: 3A2-ATG, antisense to the CVP3A2 mRNA translational start site; 3A2-REV, 5 ’ to 3 ’ reverse sequence of 3A2-ATG; and C-MYC, antisense to the C-MYC mRNA translational start site. Midazo-lam (MZ) sleep times were used as CYP3A2-specific in vivo marker in male Sprague-Dawley rats. Administration of 1 mgI day 3A2-ATG for 2 days i.p. significantly increased MZ sleep times from 22.4 ± 0.4 (saline) to 35.3 ± 1.5 mm. Administration of equivalent doses of noncomplementary 3A2-REV or C-MYC produced no significant changes in MZ sleep times (22.4 ± 0.