Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Vet Dermatol. 2023 Jun;34(3):222-234. doi: 10.1111/vde.13109. Epub 2022 Aug 5.
Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid (MPA) which acts as an immunosuppressive agent. During the biotransformation of MMF to MPA, additional metabolites including MPA phenol glucuronide (MPAG), MPA acyl glucuronide (AcMPAG) and MPA phenol glucoside (MPG) are formed.
To define the noncompartmental pharmacokinetic (PK) parameters of three single doses of intravenous (i.v.) MMF and its downstream metabolites in healthy horses.
Six healthy Standardbred mares.
Generic MMF (Par Pharmaceuticals; Chestnut Ridge, NY, USA) was reconstituted and administered as a single i.v. bolus at 1.0 mg/kg, 5.0 mg/kg and 10.0 mg/kg with an eight day washout between treatments. Blood samples were collected immediately before MMF administration and over 24 h. A liquid chromatography-tandem mass spectrometry assay was developed following FDA guidance to determine plasma MMF, MPA, MPAG, AcMPAG and MPG concentrations. Plasma concentrations were analysed independently, followed by calculation of geometric mean and coefficient of variation.
Noncompartmental PK parameters were determined for MMF and all metabolites at all doses. MMF was rapidly converted to MPA in all horses. Each incremental dose of MMF resulted in increases in C and AUC _obs for MPA and the three additional metabolites. Within the 10-fold dose range, the increase in C and AUC _obs for MMF and its metabolites was nonlinear.
Horses biotransform MMF into MPA, MPAG, AcMPAG and MPG via the glucuronidation and glucosidation clearance pathways. Equine reference PK profiles for MPA and the metabolites, MPAG, AcMPAG and MPG were established.
霉酚酸酯（MMF）是霉酚酸（MPA）的前体药物，具有免疫抑制作用。在 MMF 生物转化为 MPA 的过程中，会形成包括 MPA 酚基葡萄糖醛酸苷（MPAG）、MPA 酰基葡萄糖醛酸苷（AcMPAG）和 MPA 酚基葡萄糖苷（MPG）在内的其他代谢物。
确定健康马单次静脉注射（i.v.）MMF 及其下游代谢物的非房室药代动力学（PK）参数。
6 匹健康的标准种母马。
使用 Par 制药公司（美国纽约州切斯特顿里奇）生产的通用 MMF 制剂，以 1.0mg/kg、5.0mg/kg 和 10.0mg/kg 的剂量单次静脉推注给药，每 8 天进行一次洗脱期。在 MMF 给药前和给药后 24 小时内采集血样。按照 FDA 指南建立了液相色谱-串联质谱检测法，以确定血浆 MMF、MPA、MPAG、AcMPAG 和 MPG 浓度。对各剂量下 MMF 及其所有代谢物的非房室 PK 参数进行独立分析，然后计算几何均数和变异系数。
确定了 MMF 及其所有代谢物在各剂量下的非房室 PK 参数。在所有马中，MMF 迅速转化为 MPA。随着 MMF 剂量的递增，MPA 及其 3 种额外代谢物的 C 和 AUC _obs 也随之增加。在 10 倍剂量范围内，MMF 及其代谢物的 C 和 AUC _obs 增加是非线性的。
马通过葡萄糖醛酸化和葡萄糖苷酸化清除途径将 MMF 转化为 MPA、MPAG、AcMPAG 和 MPG。建立了 MPA 及其代谢物、MPAG、AcMPAG 和 MPG 的马参考 PK 图谱。
