RESUMEN
Chlorpheniramine (CPAM) is a chiral antihistaminic drug commercialized as a racemic mixture. The intestinal absorption and metabolism of CPAM have been investigated in rat using in vivo (oral and IV administration), in situ (intestinal loop model), and in vitro (everted sac model) experiments. Oral and IV administrations of 20 mg/kg of the racemic mixture show that the pharmacokinetics of CPAM are stereoselective, with higher AUCs for the (+)-S-enantiomer compared to its antipode. The monodesmethyl metabolite (DCPM) was quantifiable in blood and its pharmacokinetics are stereoselective after oral but not after IV administration. Experiments using intestinal loops and everted sacs showed that the absorption is not stereoselective and that in vivo stereoselective formation of DCPM is presumably due to stereoselective hepatic metabolism. Moreover, the in vitro and in situ absorption of CPAM are not modified by modulators of P-glycoprotein and cytochromes P450 (cyclosporin A, ketoconazole).
Asunto(s)
Clorfeniramina/metabolismo , Clorfeniramina/farmacocinética , Animales , Clorfeniramina/química , Ciclosporina/farmacología , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/metabolismo , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Técnicas In Vitro , Absorción Intestinal/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , EstereoisomerismoRESUMEN
The in vitro binding of RS-chlorpheniramine to human proteins was studied by equilibrium dialysis. The binding to total plasma proteins and to individual albumin and alpha-glycoprotein acid is stereoselective. (+)S-chlorpheniramine is more extensively bound than its antipode to total plasma proteins (38% vs. 23%), to albumin (20% vs. 15%) and to alpha-glycoprotein acid (23% vs. 5%).
Asunto(s)
Proteínas Sanguíneas/metabolismo , Clorfeniramina/sangre , Clorfeniramina/química , Clorfeniramina/farmacocinética , Humanos , Técnicas In Vitro , Orosomucoide/metabolismo , Unión Proteica , Albúmina Sérica/metabolismo , EstereoisomerismoRESUMEN
The enantiomers of chlorpheniramine and its monodesmethyl metabolite were determined separately in urine by using a coupled achiral-chiral chromatographic system. The two enantiomers of the studied compound and the internal standard were separated from the biological matrix on a cyanopropyl column and reinjected into a chiral amylose AD column where the two enantiomers were separated and quantified by UV detection. The method was validated for chlorpheniramine and for the metabolite within the range 0-1000 ng/ml. It was also applied in a pilot pharmacokinetic study to samples from a volunteer given 8 mg of racemic chlorpheniramine by mouth.
