Molloy Billy, Mullin Lauren, King Adam, Gethings Lee A, Plumb Robert S, Wilson Ian D
Waters Corporation, Stamford Rd, Wilmslow SK9 4AX, UK.
Waters Corporation, Milford, MA 01757, USA.
Metabolites. 2021 Jun 11;11(6):379. doi: 10.3390/metabo11060379.
The effects of intravenous gefitinib (10 mg/kg), an anilinoquinazoline thymidylate kinase inhibitor (TKI), selective for the epidermal growth factor receptor (EGFR), on the urinary metabotypes of mice were studied. We hypothesized that, in response to the administration of gefitinib, there might be significant changes in the excretion of many endogenous metabolites in the urine, which could be correlated with the plasma pharmacokinetics (PK) of the drug. In order to investigate this conjecture, urine from male C57 BL6 mice was collected before IV dosing (10 mg/kg) and at 0-3, 3-8, and 8-24 h post-dose. The samples were profiled by UPLC/IM/MS and compared with the profiles obtained from undosed control mice with the data analyzed using multivariate statistical analysis (MVA). This process identified changes in endogenous metabolites over time and these were compared with drug and drug metabolite PK and excretion. While the MVA of these UPLC/IM/MS data did indeed reveal time-related changes for endogenous metabolites that appeared to be linked to drug administration, this analysis did not highlight the presence of either the drug or its metabolites in urine. Endogenous metabolites affected by gefitinib administration were identified by comparison of mass spectral, retention time and ion mobility-derived collision cross section data (compared to authentic standards wherever possible). The changes in endogenous metabolites resulting from gefitinib administration showed both increases (e.g., tryptophan, taurocholic acid, and the dipeptide lysyl-arginine) and decreases (e.g., deoxyguanosine, 8-hydroxydeoxyguanosine, and asparaginyl-histidine) relative to the control animals. By 8-24 h, the post-dose concentrations of most metabolites had returned to near control values. From these studies, we conclude that changes in the amounts of endogenous metabolites excreted in the urine mirrored, to some extent, the plasma pharmacokinetics of the drug. This phenomenon is similar to pharmacodynamics, where the pharmacological effects are related to the drug concentrations, and by analogy, we have termed this effect "pharmacometabodynamics".
研究了静脉注射吉非替尼（10毫克/千克）对小鼠尿液代谢型的影响。吉非替尼是一种对表皮生长因子受体（EGFR）具有选择性的苯胺喹唑啉胸苷酸激酶抑制剂（TKI）。我们推测，在给予吉非替尼后，尿液中许多内源性代谢物的排泄可能会发生显著变化，这可能与药物的血浆药代动力学（PK）相关。为了研究这一推测，在静脉给药（10毫克/千克）前以及给药后0 - 3小时、3 - 8小时和8 - 24小时收集雄性C57 BL6小鼠的尿液。通过超高效液相色谱/离子淌度/质谱联用（UPLC/IM/MS）对样品进行分析，并与未给药对照小鼠的图谱进行比较，使用多变量统计分析（MVA）对数据进行分析。这一过程确定了内源性代谢物随时间的变化，并将这些变化与药物及药物代谢物的PK和排泄情况进行比较。虽然对这些UPLC/IM/MS数据的MVA确实揭示了内源性代谢物与给药相关的时间变化，但该分析并未突出尿液中药物或其代谢物的存在。通过比较质谱、保留时间和离子淌度衍生的碰撞截面数据（尽可能与真实标准品比较），确定了受吉非替尼给药影响的内源性代谢物。与对照动物相比，吉非替尼给药导致的内源性代谢物变化既有增加（如色氨酸、牛磺胆酸和二肽赖氨酰 - 精氨酸），也有减少（如脱氧鸟苷、8 - 羟基脱氧鸟苷和天冬酰胺 - 组氨酸）。到8 - 24小时，大多数代谢物的给药后浓度已恢复到接近对照值。从这些研究中，我们得出结论，尿液中排泄的内源性代谢物量的变化在一定程度上反映了药物的血浆药代动力学。这种现象类似于药效学，其中药理作用与药物浓度相关，以此类推，我们将这种效应称为“药物代谢动力学”。
