The Effect of Pregnenolone 16α-Carbonitrile on the Pharmacokinetics and Metabolism of Dapsone in Rats

Abstract

Abstract The purpose of this study was to evaluate the effect of pregnenolone 16α-carbonitrile (PCN) on the interconversion pharmacokinetics and metabolism of dapsone. To determine microsomal CYP3A activity and protein, eight rats (4 PCN, 4 corn oil) received a 1mg kg−1 intravenous bolus dose of dapsone, followed by blood and urine sampling. The formation clearance of dapsone hydroxylamine (CLf DDS-NOH) was calculated from the obtained samples. Interconversion pharmacokinetics estimates were obtained after 10 rats (5 PCN, 5 control) received 1mg kg−1 dapsone or 1.17 mg kg−1 monoacetyldapsone, with a 24-h wash-out. Results from the interconversion analysis demonstrated that PCN significantly increased systemic clearance (CLs) of dapsone, but not its interconversion. The in-vivo/in-vitro correlation study demonstrated that PCN significantly increased CLs of dapsone (8.55 to 16.39mL min−1; P <0.01) and CLf DDS-NOH (0.13 to 0.18mL min−1; P < 0.01). PCN treatment produced a 69% increase in CYP3A protein, and increased 6β- and 2β-hydroxytestosterone formation rates. Significant correlations were found between CLf DDS-NOH and either 6β- (r2 = 0.925), 2β-hydroxytestosterone (r2 = 0.92), or CYP3A1/2 protein (r2 = 0.60). We conclude that PCN treatment produces significant increases in CLs (dapsone) and CLf (DDS-NOH) in rats. These changes were not due to changes in the reversible metabolism of dapsone. These results suggest that the formation clearance of dapsone hydroxylamine reflects alterations in CYP3A activity, despite the fact that it accounted for a small part of the systemic clearance of dapsone.