Hiep B T, Fernandez C, Tod M, Banide H, Thuillier A, Lacour B, Farinotti R, Gimenez F
Faculté de Pharmacie, UPRES 2706, Châtenay-Malabry, France.
Chirality. 2001 May 5;13(4):207-13. doi: 10.1002/chir.1021.
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).
氯苯那敏（CPAM）是一种作为外消旋混合物商业化的手性抗组胺药物。已在大鼠中使用体内（口服和静脉注射）、原位（肠袢模型）和体外（外翻肠囊模型）实验研究了CPAM的肠道吸收和代谢。口服和静脉注射20mg/kg外消旋混合物表明，CPAM的药代动力学具有立体选择性，（+）-S-对映体的AUCs高于其对映体。单去甲基代谢物（DCPM）在血液中可定量，其药代动力学在口服后具有立体选择性，但静脉注射后不具有立体选择性。使用肠袢和外翻肠囊的实验表明，吸收没有立体选择性，体内DCPM的立体选择性形成可能是由于肝脏的立体选择性代谢。此外，CPAM的体外和原位吸收不受P-糖蛋白和细胞色素P450调节剂（环孢素A、酮康唑）的影响。
