Charasson Virginie, Haaz Marie-Christine, Robert Jacques
Institut Bergonié, BORDEAUX-cedex, France.
Drug Metab Dispos. 2002 Jun;30(6):731-3. doi: 10.1124/dmd.30.6.731.
Irinotecan or CPT-11 [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] is a derivative of camptothecine used in the treatment of advanced colorectal cancer. It requires activation to SN-38 (7-ethyl-10-hydroxycamptothecine) by carboxylesterase. Irinotecan and SN-38 are detoxified through two major metabolic pathways: the first one leads to oxidative degradation compounds, APC [7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecine] and NPC [7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine], and involves cytochrome P450 (3A4 isoform); the second one leads to SN-38 glucuronide (SN-38G) and involves UDP-glucuronosyltransferase (UGT). Using human hepatic microsomes, we studied the interactions of 15 drugs of common use in colorectal cancer patients on these metabolic pathways. Only nifedipine had a significant effect on SN-38 formation, decreasing carboxylesterase activity by 50% at 100 microM and 35% at 10 microM. Three drugs had a significant effect on SN-38G formation: clonazepam increased UGT activity by 50% at 100 microM and 30% at 10 microM, and nifedipine and vinorelbine inhibited the activity by 65 and 55% at 100 microM, respectively, with no effect at 10 microM. Five drugs exerted a significant inhibition on SN-38 formation at 100 microM: clonazepam (70%), methylprednisolone (50%), nifedipine (80%), omeprazole (85%), and vinorelbine (100%). Only omeprazole and vinorelbine still exerted a significant inhibition at 10 microM (30 and 90%, respectively), whereas only vinorelbine had a significant effect at 2 and 0.5 microM (70 and 40%, respectively). In conclusion, potential clinical interactions with the metabolism of irinotecan are likely to be important for vinorelbine, which strongly inhibits irinotecan catabolism by CYP3A4 at clinically relevant concentrations, but not for the other drugs, which exert an effect at concentrations not achievable in patients.
伊立替康或CPT - 11[7 - 乙基 - 10 - [4 - (1 - 哌啶基)-1 - 哌啶基]羰基氧基喜树碱]是一种用于治疗晚期结直肠癌的喜树碱衍生物。它需要通过羧酸酯酶激活为SN - 38（7 - 乙基 - 10 - 羟基喜树碱）。伊立替康和SN - 38通过两条主要代谢途径解毒：第一条途径导致氧化降解化合物APC[7 - 乙基 - 10 - [4 - N - (5 - 氨基戊酸)-1 - 哌啶基]羰基氧基喜树碱]和NPC[7 - 乙基 - 10 - (4 - 氨基 - 1 - 哌啶基)羰基氧基喜树碱]的形成，该途径涉及细胞色素P450（3A4同工型）；第二条途径导致SN - 38葡萄糖醛酸苷（SN - 38G）的形成，该途径涉及尿苷二磷酸葡萄糖醛酸基转移酶（UGT）。我们使用人肝微粒体研究了15种结直肠癌患者常用药物在这些代谢途径上的相互作用。只有硝苯地平对SN - 38的形成有显著影响，在100微摩尔时羧酸酯酶活性降低50%，在10微摩尔时降低35%。三种药物对SN - 38G的形成有显著影响：氯硝西泮在100微摩尔时使UGT活性增加50%，在10微摩尔时增加30%，硝苯地平和长春瑞滨在100微摩尔时分别抑制该活性65%和55%，在1微摩尔时无影响。五种药物在100微摩尔时对SN - 38的形成有显著抑制作用：氯硝西泮（70%）、甲泼尼龙（50%）、硝苯地平（80%）、奥美拉唑（85%）和长春瑞滨（100%）。只有奥美拉唑和长春瑞滨在10微摩尔时仍有显著抑制作用（分别为30%和90%），而只有长春瑞滨在2微摩尔和0.5微摩尔时有显著影响（分别为70%和40%）。总之，与伊立替康代谢的潜在临床相互作用对长春瑞滨可能很重要，长春瑞滨在临床相关浓度下强烈抑制CYP3A4介导的伊立替康分解代谢，但对其他药物而言，它们在患者无法达到的浓度下才发挥作用，因此不太重要。
