Ex vivo binding of the immunosuppressant mycophenolic acid to dog and cat plasma proteins and the effect of co‐incubated dexamethasone and prednisolone

Abstract

Mycophenolic acid (MPA) has been shown to be promising for the treatment of autoimmune diseases in dogs and cats. In humans, MPA is highly bound to plasma proteins (~97%). It has been recommended to monitor free drug plasma concentrations because the free MPA correlates with its immunosuppressive effect. However, it is unknown if MPA is highly bound to plasma proteins in dogs and cats. The objectives of this study were to determine the extent of plasma protein binding of MPA and evaluate the effect of prednisolone and dexamethasone on the extent of protein binding of MPA in dogs and cats. The extent of plasma protein binding of MPA was determined in plasma collected from clinically healthy adult cats (n = 13) and dogs (n = 14) by combining high-throughput dialysis and ultra-high-liquid chromatography. This study reveals that MPA is highly bound to plasma proteins (>90%) in dogs and cats, mean extent of binding of MPA at 15 μg/ml to plasma proteins being 96% (range, 95%-97%) and 92% (range, 90%-93%) for dogs and cats, respectively. In dog plasma, MPA is primarily bound to albumin. In vitro, prednisolone increased the unbound MPA in dogs (p < .01) but not in cats (p = .07) while dexamethasone had no effect on MPA plasma binding in either species (p > .05). Results of this study provide valuable information for designing future pharmacokinetic and pharmacodynamic studies and also therapeutic monitoring programs for dogs and cats.

Canine Albumin Polymorphisms and Their Impact on Drug Plasma Protein Binding

“…Our results were consistent with the mean extent of plasma protein binding previously reported for dogs (99.9% for D01-4582, 97% for meloxicam, 98.5% for celecoxib, and 95%–97% for mycophenolic acid) (Busch et al, 1998; Paulson et al, 1999b; Ito et al, 2009; Morassi et al, 2018). For D01-4582, our findings differ from a previous report (Ito et al, 2009) in which free drug fractions were greater in plasma from Beagles with the albumin H2 allele than in plasma from Beagles with the H1 allele.…”

“…The remaining compounds were selected based on their reported high plasma protein binding (>95%), site-specific binding to human albumin (Er et al, 2013), and previous clinical use in dogs (Table 1). The method (ultracentrifugation or equilibrium dialysis) used to determine the extent of each drug plasma binding was primarily selected based on methods previously reported for that drug Jolliet et al, 1997; Lapicque et al, 2000; Ito et al, 2009; Cooper et al, 2014; Morassi et al, 2018).…”

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

“…After PO administration, MMF undergoes rapid presystemic tissue de‐esterification and is converted to the active metabolite MPA . In cats, MPA is highly bound to plasma proteins, and is eliminated from the body rapidly likely by hepatic biotransformation into at least 2 metabolites: MPA phenol glucoside (MPAGls) and MPA phenol glucuronide (MPAG) …”

“…7,15 After PO administration, MMF undergoes rapid presystemic tissue de-esterification [15][16][17] and is converted to the active metabolite MPA. 15 In cats, MPA is highly bound to plasma proteins, 18 and is eliminated from the body rapidly likely by hepatic biotransformation into at least 2 metabolites: MPA phenol glucoside (MPAGls) and MPA phenol glucuronide (MPAG). 19,20 The primary action of MPA involves decreasing T and B lymphocyte proliferation by a specific and noncompetitive mechanism of action that decreases production of antibodies, decreases proliferation of CD4 + and CD8 + lymphocytes, and inhibits adhesion of glycoproteins to endothelial cells.…”