Pharmacokinetics of mycophenolic acid and its phenyl glucuronide metabolite in kidney transplant recipients with renal impairment proliferation of T and B lymphocytes, preventing the acute rejection of a transplanted organ as well as decreasing the frequency of late rejection after one year and consecutive years [2, 3]. The MPA undergoes enterohepatic recirculation. It is con- verted into an inactive phenyl glucuronide (MPAG), which is excreted into bile and hydrolysed into MPA in the presence of β-glucuronidase, produced by intestinal bacteria, and subsequently reabsorbed in the intestines. It was found that, on average, the enterohepatic recirculation takes part in about 40% (10-60%) of the entire MPA exposure [4]. The MPA as well as MPAG pharmacokinetics (PK) show great inter-patient variability depend- ing on race, sex, concomitant clinical condition (e.g. kidney or liver impairment, diseases with coexist- ing hypoalbuminaemia), interactions with drugs influencing the PK of MPA and MPAG, time elapsed after renal transplantation and pharmacogenetic factors [4-6]. The MPAG is eliminated mainly by the kidney and the increase of its concentration may indi- cate the deterioration of renal function. Compared to patients with normal renal function, MPAG con- centration in patients with impaired renal func- tion is several times greater. Uncontrolled MPAG concentration increase causes MPA displacement from protein compounds and the increase of free MPA, which might be the cause of higher phar- macological activity of the drug and the intensi- fication of its adverse effects. The influence of renal failure on total MPA concentration is still unclear. There are no unequivocal recommenda- Table I. Characteristics of study patients Number of patients Male/female CsA/Tac Corticosteroid use Proteinuria (yes/no) Median (range) Age [years] Time after transplantation [years] Body weight [kg] Body mass index [kg/m2] Body surface area [m2] MMF dose [g/day] CsA dose [mg/day] Tac dose [mg/day] Serum creatinine [mg/dl] Ccr [ml/min]** All (n = 43) 23/20 21/22 36 9/34 44 (23-69) 4.1 (0.6-10.9) 74 (44-109) 25.2 (16.1-36.8) 1.86 (1.37-2.35) 1.50 (0.50-2.00) 175 (75-275) 4 (1-12) 1.7 (0.8-4.8) 53.7 (20.4-114.7) tions for MMF dosing in patients with renal fail- ure [4, 7, 8]. The aim of the study was to analyse the influ- ence of renal impairment on the PK of MPA and its metabolite MPAG in renal transplant recipients. Material and methods Forty-three adult patients during the mainte- nance period (> 6 months) following renal trans- plantation receiving MMF in combination with cyclosporine (CsA) (n = 21) or tacrolimus (Tac) (n = 22) and corticosteroids were considered. The MMF dose varied from 0.50 g/day to 2.00 g/day and was administered most often twice a day. The study included patients with normal renal function (n = 16; creatinine clearance (Ccr) > 60 ml/min) and with renal impairment (n = 27, Ccr < 60 ml/min). Clinical characteristics of the patients are present- ed in Table I. Blood samples were collected into tubes containing EDTA at the following time points: before the morning dose of MMF (C0), and subse- quently 40 min, 1, 2, 3, 4 h after dosing. Plasma MPA and MPAG concentrations were determined using a high-performance liquid chro- matography (HPLC) method described previously [9, 10]. Briefly, the separation was performed using a SupelcosilTM LC-18-DB column. The mobile phase consisted of acetonitrile and orthophosphoric acid (50 mmol/l) in a 50 : 50 ratio and indomethacin was used as an internal standard. The MPAG plasma concentration was estimated after MPAG enzymatic hydrolysis into MPA in β-glucuronidase presence (activity 89.4 U/ml). The MPAG concentrations were Ccr > 60 ml/min (n = 17) Ccr < 60 ml/min (n = 26) 11/6 8/9 12 1/16 44 (24-57) 3.8 (0.6-10.8) 75 (47-109) 25.8 (21.2-36.5) 1.89 (1.37-2.35) 1.00 (1.00-2.00) 162.5 (100-250) 4 (1-12) 1.3 (0.8-1.7) 75.2 (60.5-114.7) 12/14 13/13 24 8/18 44 (23-69) 4.4 (1.2-10.9) 73.5 (44-105) 23.7 (16.1-36.8) 1.85 (1.39-2.22) 1.50 (0.50-2.00) 175 (75-275) 4 (2-9) 2.1 (1.0-4.8)* 44.9 (20.4-59.7)* Ccr – creatinine clearance, CsA – cyclosporine, Tac – tacrolimus, MMF – mycophenolate mofetil, *p < 0.05, patients with Ccr > 60 ml/min vs. < 60 ml/min, Mann-Whitney test, **estimated by the Cockcroft-Gault equation Arch Med Sci 1, February / 2012 89