Pharmacokinetics of mycophenolic acid and its phenyl-glucuronide in kidney transplant recipients with renal insufficiency

Background: The aim of the study was to analyze the influence of renal insufficiency on the pharmacokinetics of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) in kidney transplant patients.
Material/Methods: The study included 43 adult patients at least one year after renal transplantation (from 1 to 11 years), treated with mycophenolate mofetil (MMF) and tacrolimus or cyclosporine and steroids. They were divided into a group with normal renal function (n=16; creatinine clearance [Cl[sub]cr[/sub]] >60 ml/min) and one with renal insufficiency (n=27, Cl[sub]cr[/sub]<60 ml/min). Areas under the 4-hour curve (AUC[sub]0-4h[/sub]) of MPA and MPAG were determined using a validated HPLC method.
Results: The renal insuffi ciency group showed significantly increased AUC[sub]0-4[/sub] and trough levels for MPAG (543.1±366.1 vs. 273.9±113.2 mg-h/ml, p=0.002, and 106.0±78.5 vs. 42.8±22.5 mg/ml, p=0.0002, respectively) and increased trough level of MPA (p=0.01). There was a significant correlation between MPAG AUC[sub]0-4[/sub] or C[sub]0[/sub] and Cl[sub]cr[/sub] (r=±0.592, p<0.00001 and r=-0.698, p<0.00001, respectively). There was no significant difference in MPA AUC[sub]0-4 [/sub]between the renal insufficiency and the normal renal function groups.
Conclusions: Although MPAG is an inactive metabolite, its accumulation in patients with renal impairment can be unfavorable. MPAG has been shown to displace MPA from protein binding sites increasing MPA free fraction without changing total MPA AUC. This should be taken into account when deciding upon MMF dose in patients with renal failure with unexpected side effects.

Keywords: Pharmacokinetics, Mycophenolic Acid, renal transplantation, Tacrolimus