Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14214, USA.
Biopharm Drug Dispos. 2013 May;34(4):203-14. doi: 10.1002/bdd.1838. Epub 2013 Apr 7.
Methotrexate (MTX) is an anchor drug used to treat rheumatoid arthritis (RA), but responsiveness is variable in effectiveness and toxicity. Methotrexate and its polyglutamate conjugates (MTXPG(n)) in red blood cells (RBC) have been associated with patient response. In the current study, 13 collagen-induced arthritic (CIA) rats and 12 healthy rats were given subcutaneous doses of either saline or 0.3 or 1.5 mg/kg per 2 days of MTX from day 21 to 43 post-induction. Blood samples were obtained at various times to measure MTX in plasma, and MTX and MTXPG(n) in RBC. Effects on disease progression were indicated by body weight and paw size. After multiple-doses, RBC MTX reached steady-state (82.4 nm) within 4 days. The MTXPG(2) and MTXPG(3) in RBC kept increasing until the end of the study, attaining 12.5 and 17.7 nm. Significant weight loss was observed after dosing with 1.5 mg/kg/2 days, whereas moderate effectiveness was observed after dosing with 0.3 mg/kg/2 days. A pharmacokinetic/pharmacodynamic/disease (PK/PD/DIS) model with indirect mechanisms and transduction components incorporating plasma MTX, RBC MTX and RBC MTXPG(n) concentrations, and paw size was developed using naïve data pooling and ADAPT 5. The PK/PD in CIA rats dosed at 0.3 mg/kg/2 days were captured well by our proposed model. Methotrexate showed modest (I(maxd) = 0.16) but sensitive (IC(50d) = 0.712 nm) effectiveness on paw edema. The higher dose produced toxicity. The proposed model offers improved understanding of the effects of methotrexate on rheumatoid arthritis.
甲氨蝶呤（MTX）是一种用于治疗类风湿关节炎（RA）的锚定药物，但在有效性和毒性方面的反应性各不相同。红细胞（RBC）中的 MTX 及其多聚谷氨酸缀合物（MTXPG(n)）与患者的反应有关。在当前的研究中，从诱导后第 21 天到第 43 天，13 只胶原诱导性关节炎（CIA）大鼠和 12 只健康大鼠每天接受 0.3 或 1.5mg/kg 甲氨蝶呤的皮下剂量。在不同时间采集血液样本以测量血浆中甲氨蝶呤的浓度，以及 RBC 中的 MTX 和 MTXPG(n)。通过体重和爪子大小来衡量疾病进展的影响。多次给药后，RBC 中甲氨蝶呤在 4 天内达到稳态（82.4nm）。RBC 中的 MTXPG(2)和 MTXPG(3) 持续增加，直到研究结束，达到 12.5nm 和 17.7nm。每天 1.5mg/kg/2 天给药后观察到明显的体重减轻，而每天 0.3mg/kg/2 天给药后观察到中度疗效。使用天真数据池和 ADAPT 5 开发了一个包含血浆 MTX、RBC MTX 和 RBC MTXPG(n)浓度以及爪子大小的间接机制和转导成分的 PK/PD/DIS 模型。我们提出的模型很好地捕捉了每天 0.3mg/kg/2 天给药的 CIA 大鼠的 PK/PD。甲氨蝶呤对爪肿胀显示出适度（I(maxd) = 0.16）但敏感（IC(50d) = 0.712nm）的疗效。较高的剂量会产生毒性。该模型提供了对甲氨蝶呤治疗类风湿关节炎的作用的更好理解。
