Okava Pharmaceuticals, San Francisco, CA, USA.
Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
J Vet Pharmacol Ther. 2021 Jul;44(4):650-656. doi: 10.1111/jvp.12950. Epub 2021 Feb 13.
Mycophenolic acid (MPA) is an immunomodulating agent commonly used in human medicine for the treatment of immune-mediated diseases. There is growing evidence that the immunomodulating properties of mycophenolate mofetil (MMF), a prodrug of MPA, are therapeutically beneficial for the treatment of immune-mediated diseases in dogs. A narrow therapeutic index and high inter-and intra-patient pharmacokinetic (PK) variability complicate the use of MMF. A better characterization of MPA pharmacokinetics is needed to help establish dosing regimens and standardized treatment protocols for canine patients. The purpose of this study was to evaluate the pharmacokinetics of MPA in dogs. MMF oral suspension (10 mg/kg) was administered to five healthy beagle dogs. Serial blood samples were collected from 0 to 18 hours after administration. The simultaneous quantification of MPA, and its metabolites MPA-7-O-glucuronide (MPAG), and acyl glucuronide (AcMPAG) was determined by liquid chromatography (LC)-mass spectrometry (MS)/MS. MPA peak concentrations were achieved rapidly (median Tmax of 0.5 h). Concentrations fell through 3 hours post-dose and then plateaued around 20% of Cmax. The mean elimination half-life was rapid (5.8 hours) and notable variability was observed in all PK parameters. The PK profiles for the MPAG and AcMPAG metabolites followed a similar pattern as MPA concentration. Future repeat-dose studies will be needed to evaluate steady-state PK parameters and to define therapeutic MPA dose levels.
霉酚酸（MPA）是一种免疫调节剂，常用于人类医学治疗免疫介导性疾病。越来越多的证据表明，MPA 的前体药物霉酚酸酯（MMF）的免疫调节特性对治疗犬的免疫介导性疾病具有治疗益处。狭窄的治疗指数和高个体间和个体内药代动力学（PK）变异性使 MMF 的使用复杂化。需要更好地描述 MPA 的药代动力学，以帮助为犬患者建立剂量方案和标准化治疗方案。本研究旨在评估 MPA 在犬体内的药代动力学。给 5 只健康的比格犬口服 MMF 混悬液（10mg/kg）。给药后 0 至 18 小时采集系列血样。通过液相色谱（LC）-质谱（MS）/MS 同时定量测定 MPA、其代谢物 MPA-7-O-葡糖苷酸（MPAG）和酰基葡糖苷酸（AcMPAG）。MPA 达峰迅速（中位数 Tmax 为 0.5h）。给药后 3 小时浓度下降，然后在 Cmax 的约 20%处达到平台期。平均消除半衰期较快（5.8 小时），所有 PK 参数均观察到明显的变异性。MPAG 和 AcMPAG 代谢物的 PK 特征与 MPA 浓度相似。需要进行重复剂量研究来评估稳态 PK 参数并确定治疗性 MPA 剂量水平。
