Pharmacovigilance of herb-drug interactions: A pharmacokinetic study on the combination administration of herbal Kang'ai injection and chemotherapy irinotecan hydrochloride injection by LC-MS/MS

Abstract

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 C₀ (5129 ± 757 ng/mL) and AUC_0-t (7858 ± 1307 ng h/mL) of CPT-11 in the CPT-11 single administration group, the C₀ (4574 ± 371 ng/mL) and AUC_0-t (8779 ± 601 ng h/mL) after the separated co-administration remained unchanged, but the pre-mixed co-administration resulted with a significant increased C₀ (29,454 ± 12,080 ng/mL) and AUC_0-t (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.

Keywords: Herb-drug interactions; Irinotecan hydrochloride injection; Kang’ai injection; LC–MS/MS; Pharmacokinetics; Pharmacovigilance.