The effect of pregnenolone 16alpha-carbonitrile on the pharmacokinetics and metabolism of dapsone in rats.
J Pharm Pharmacol
; 51(7): 803-10, 1999 Jul.
Article
en En
| MEDLINE
| ID: mdl-10467955
The purpose of this study was to evaluate the effect of pregnenolone 16 alpha-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 1 mg 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 1 mg 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 16.39mLmin(-1); P<0.01) and CLf DDS-NOH (0.13 to 0.18mLmin(-1); P<0.01). PCN treatment produced a 69% increase in CYP3A protein, and increased 6beta- and 2beta-hydroxytestosterone formation rates. Significant correlations were found between CLf DDS-NOH and either 6beta- (r2 = 0.925), 2beta-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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Carbonitrilo de Pregnenolona
/
Hidrocarburo de Aril Hidroxilasas
/
Dapsona
/
Antiinfecciosos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Pharm Pharmacol
Año:
1999
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido