Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing, 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China.
Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing, 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China.
J Pharm Biomed Anal. 2021 Feb 5;194:113784. doi: 10.1016/j.jpba.2020.113784. Epub 2020 Nov 20.
Chinese herbal drugs are often combined with chemotherapy drugs for the treatment of cancers. However, the combination administrations often do not have scientifically sound bases established on full preclinical and clinical investigations. A commonly used anti-colon-cancer herb-drug pair, irinotecan (CPT-11) hydrochloride injection and Kang'ai (KA) injection was taken as an example to investigate the possible pharmacokinetic interactions between Chinese herbal drugs and chemotherapy injections to determine the potential adverse drug reactions (ADRs). Rats were randomly divided into three groups and received 20 mg/kg CPT-11 injection 15 min after administration of 4 mL/kg saline for the CPT-11 single administration group and 4 mL/kg KA injection for the separated co-administration group, respectively. In the pre-mixed co-administration group, rats received a mixture of 20 mg/kg CPT-11 injection and 4 mL/kg KA injection. Blood samples were collected at 10 pre-determined time points between 0 and 24 h. The tissue samples were collected at 5 and 8 min after the injections, respectively. A reliable LC-MS/MS method was established for the simultaneous determination of CPT-11 and its metabolites, SN-38, SN-38 G and APC in the rat plasma and tissue samples, after full confirmation of two injections chemical and stability compatibilities. Compared to the C (5129 ± 757 ng/mL) and AUC (7858 ± 1307 ng h/mL) of CPT-11 in the CPT-11 single administration group, the C (4574 ± 371 ng/mL) and AUC (8779 ± 601 ng h/mL) after the separated co-administration remained unchanged, but the pre-mixed co-administration resulted with a significant increased C (29,454 ± 12,080 ng/mL) and AUC (15,539 ± 5165 ng h/mL) (p < 0.05). Since the exposures of CPT-11 in most tissues in the pre-mixed co-administration group were dramatically lower than the separated co-administration group, the increased CPT-11 plasma concentration may be produced by the delayed tissue distribution because of the encapsulation by the components contained in KA injection, such as polysaccharides. Similar differences were also found in its metabolite, SN-38 G. There are obvious herb-drug interactions between CPT-11 injection and KA injection after the pre-mixed co-administration. The resulting excessive CPT-11 in the plasma may lead to many serious ADRs. Therefore, the full evaluation of herb-drug interactions is necessary and inappropriate combinations should be avoided.
中草药常与化疗药物联合用于癌症治疗。然而，联合用药往往没有充分的临床前和临床研究依据。以盐酸伊立替康（CPT-11）注射液和康艾注射液这一对常用的抗结肠癌草药-药物组合为例，研究中草药与化疗注射剂之间可能存在的药代动力学相互作用，以确定潜在的药物不良反应（ADR）。
将大鼠随机分为三组，分别给予 4 mL/kg 生理盐水（CPT-11 单药组）、4 mL/kg 康艾注射液（分离合用组）和 20 mg/kg CPT-11 注射液加 4 mL/kg 康艾注射液混合液（预混合合用组），15 min 后分别给予 20 mg/kg CPT-11 注射液。在 0 到 24 小时之间的 10 个预定时间点采集血样，分别在注射后 5 和 8 分钟采集组织样本。在充分确认两种注射剂的化学和稳定性相容性后，建立了一种可靠的 LC-MS/MS 方法，用于同时测定大鼠血浆和组织样本中 CPT-11 及其代谢物 SN-38、SN-38G 和 APC。
与 CPT-11 单药组的 C（5129±757 ng/mL）和 AUC（7858±1307 ng h/mL）相比，分离合用组的 C（4574±371 ng/mL）和 AUC（8779±601 ng h/mL）保持不变，但预混合合用组的 C（29454±12080 ng/mL）和 AUC（15539±5165 ng h/mL）显著增加（p<0.05）。由于预混合合用组大多数组织中 CPT-11 的暴露量明显低于分离合用组，因此，由于 KA 注射液中包含的成分（如多糖）的包裹作用，导致 CPT-11 在血浆中的分布延迟，从而导致 CPT-11 血浆浓度升高。在其代谢物 SN-38G 中也发现了类似的差异。CPT-11 注射液和康艾注射液预混合合用后存在明显的草药-药物相互作用。血浆中过多的 CPT-11 可能导致许多严重的不良反应。因此，有必要对草药-药物相互作用进行全面评估，并避免不适当的联合用药。
