The effect of pregnenolone 16 alpha-carbonitrile on the pharmacokinetics and metabolism of dapsone in rats

The purpose of this study was to evaluate the effect of pregnenolone 16 alp ha-carbonitrile (PCN) on the interconversion pharmacokinetics and metabolis m of dapsone. To determine microsomal CYP3A activity and protein, eight rat s (4 PCN, 4 corn oil) received a 1 mg kg(-1) intravenous bolus dose of daps one, followed by blood and urine sampling. The formation clearance of dapso ne hydroxylamine (CLf DDS-NOH) was calculated from the obtained samples. In terconversion pharmacokinetics estimates were obtained after 10 rats (5 PCN , 5 control) received 1 mg kg(-1) dapsone or 1.17 mg kg(-1) monoacetyldapso ne, with a 24-h wash-out. Results from the interconversion analysis demonstrated that PCN significant ly increased systemic clearance (CLs) of dapsone, but not its interconversi on. The in-vivo/in-vitro correlation study demonstrated that PCN significan tly increased CLs of dapsone (8.55 to 16.39 mL min(-1): P < 0.01) and CLf D DS-NOH (0.13 to 0.18 mL min(-1) P < 0.01). PCN treatment produced a 69% inc rease in CYP3A protein, and increased 6 beta- and 2 beta-hydroxytestosteron e formation rates. Significant correlations were found between CLf DDS-NOH and either 6 beta- (r(2) = 0.925), 2 beta-hydroxytestosterone (r(2) = 0.92) , or CYP3A1/2 protein (r(2) = 0.60). We conclude that PCN treatment produces significant increases in CLs (dapso ne) 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 cleara nce of dapsone.