Pharmacokinetics of mycophenolic acid and its effect on CD4⁺ and CD8⁺ T cells after oral administration of mycophenolate mofetil to healthy cats

Abstract

Background Mycophenolate mofetil (MMF) is an immunosuppressant used in human and veterinary medicine. Little pharmacokinetic and pharmacodynamic information on MMF is available in cats. Objective To evaluate the plasma disposition of mycophenolic acid (MPA) and assess its effect on total peripheral blood mononuclear cells and CD4+/CD8+ ratios after PO administration of MMF. Animals Healthy cats (n = 10). Methods Mycophenolate mofetil was administered at a dosage of 10 mg/kg q12h (n = 3), 15 mg/kg q12h (n = 3), and 15 mg/kg q8h (n = 4) for 7 days. Concentrations of MPA and derivatives were determined using ultra‐high‐performance liquid chromatography. Flow cytometry was used to assess CD4+/CD8+ T‐cell ratios. Results All cats biotransformed MMF into MPA. Half of the cats (5/10) had adverse effects within 1 week of MMF administration. Area under the curve limit of quantification (AUC0‐LOQh) of MPA ranged from 1.27 to 2.03 hours·μg/mL and from 1.77 to 8.54 hours·μg/mL after the first and last PO dose of 10 mg/kg. The AUC0‐loqh of MPA ranged from 2.18 to 31 hours·μg/mL after the first dose of 15 mg/kg of MMF. Before the first dose of MMF, the average total number of PBMC ranged from 1.2 to 9.3 million/mL. At the last dose of MMF, the average total number of PBMC ranged from 3 to 5 million/mL. Conclusion Mycophenolic acid was detected in all cats. The dose 10 mg/kg given q12h for 1 week was tolerated (n = 3). The efficacy of MMF as an immunosuppressant and long‐term safety in cats of this dosage regimen is unknown.

Successful treatment and long-term follow up of idiopathic immune-mediated polyarthritis with mycophenolate mofetil in a cat

“…The side effects of MMF have been reported to occur in a dose-dependent manner, and up to 10 mg/kg q12h PO can be tolerated in cats. 8 , 9 Moreover, this dosage was reported to be effective in cats with IMHA without significant side effects for 2 months. 10 In this case, MMF at a dosage of 10 mg/kg q12h PO led to complete remission of IMPA, and no side effects were observed during the treatment period of >2 years.…”

“…Recently, there have been some reports on the safety and pharmacokinetics of MMF in healthy cats. 8 , 9 , 11 , 12 In cats, when MMF is orally administered, it is absorbed in the intestine and rapidly converted to MPA in the plasma. 9 , 11 , 12 It is then bound to plasma proteins, rapidly metabolised by hepatocytes and excreted mainly in urine.…”

“… 10 , 15 Side effects were not observed in this case where treatment lasted for >2 years, indicating that previously reported doses of MMF do not necessarily cause side effects in long-term administration owing to inter-individual variability in the metabolism of MMF in cats. 8 , 9 MMF has been recommended as the first choice for additional immunotherapy in canine IMPA. 6 Similarly, in cats with IMPA, MMF may be a relatively safe and effective additional immunosuppressant when other drugs are inadequate.…”

“… 8 , 9 It is reported that MMF is absorbed from intestines and biotransformed to MPA after oral administration in healthy cats. 8 Moreover, MMF was reported to be effective in cats with IMHA without significant side effects. 10 Therefore, MMF may be one of the safe and effective treatments for immune-mediated diseases in cats.…”

Mycophenolate mofetil reduces epidural fibrosis by regulating TGF-β1/Smad2/3 axis to repress the proliferation, migration and differentiation of fibroblasts

“…Mycophenolate mofetil (MMF) is a kind of immunosuppressant that is mainly used to prevent rejection and treat refractory rejection in patients with allogeneic kidney transplantation [15]. Recently, many experiments have reported that MMF has a therapeutic effect on a variety of brotic diseases [16][17][18].…”