Table VI. Cont. Independent variables MPAG AUC0-4 h/dose [mg × h/l/g] MPAG AUC0-4 h/dose [mg × h/l/g] Sex [men/women] Body weight [kg] CNI [CsA/Tac] Ccr [ml/min] Ccr [ml/min] Proteinuria [yes/no] MPAG Cmax [mg/l] Sex [men/women] Body weight [kg] Ccr [ml/min] MPAG Cmax [mg/l] Ccr [ml/min] Proteinuria [yes/no] Relation Positive Positive Positive Negative Negative NS Positive Positive Negative Negative NS < 0.001 < 0.001 0.015 < 0.001 < 0.001 0.501 < 0.001 < 0.001 < 0.001 < 0.001 0.861 Partial value of p Model value of p Model R coefficient < 0.001 0.886 < 0.001 < 0.001 0.001 0.583 0.782 0.524 Pharmacokinetics of mycophenolic acid and its phenyl glucuronide metabolite in kidney transplant recipients with renal impairment MPAG – 7-O-mycophenolic acid glucuronide, PK – pharmacokinetic, C0 – pre-dose concentration, CNI – calcineurin inhibitor, CsA – cyclosporine, Tac – tacrolimus, MMF – mycophenolate mofetil, Ccr – creatinine clearance, NS – not significant, AUC – area under the concentration-time curve, Cmax – maximum concentration clinic. The MPA C0 is the most often used parame- ter in clinical practice. Its value may be consider- ably influenced by MPAG enterohepatic recircula- tion, resulting in the second MPA plasma concentration peak (Cmax2) approximately 6-12 h after drug administration. In our study, higher MPA C0 as well as MPAG C0, Cmax and AUC0-4 h values were observed in patients with impaired renal func- tion regardless of CNI used, whereas there were no differences in the values of the other MPA PK parameters (Cmax and AUC0-4 h). Elevated MPA C0 values may indicate intensified enterohepatic recir- culation due to MPAG concentration increase in patients with impaired renal function. The correla- tions between renal function and MPAG concen- trations as well as MPA C0 suggest that the cause of the differences observed between two groups is the dependence of MPAG concentration and indi- rectly MPA C0 on renal function. The results con- cerning MPAG are consistent with the literature. However, the influence of renal function on MPA PK parameters is still unclear. Similar results concerning MPA and MPAG PK parameters were obtained by Gonzalez-Roncero et al. [14]. The authors demonstrated not only the influence of renal function on MPA C0 and MPAG AUC but also its lack on MPA AUC. The studies by Zanker et al. [15], Morgera et al. [16] and Weber et al. [17] also observed higher MPAG AUC in renal transplant recipients with lower Ccr than in patients with normal glomerular filtration. However, values of MPA AUC did not differ significantly. On the oth- er hand, the results for MPA obtained by Moham- madpur et al. [18] were different. According to this study, significantly higher MPA AUC0-12 h values along with unchanged C0 and significantly higher MPA Cmax2 values were observed in patients with impaired renal function. The authors also found a negative correlation for Ccr and MPA AUC. The use of abbreviated MPA profiles in our study may be the reason for different AUC results compared with the Mohammadpur et al. study. The abbreviated profiles do not include MPA Cmax2 associated with enterohepatic recirculation. In contrast to these studies, van Hest et al. [19] and Weber et al. [20] observed a total MPA concentration decrease in patients with impaired renal function. It was sug- gested that the concentration decrease was due to the accumulation of MPAG, which displaced MPA from its protein compounds, increasing free MPA concentration and its clearance. The controversies concerning the influence of renal failure on MPA concentration values may be explained by Naesens et al. [21]. The authors observed increased MPA and MPAG concentration values in patients with mod- erately reduced renal function (Ccr ranging from 30 ml/min to 60 ml/min), whereas decreased total MPA concentration values were observed in pa- tients with severe graft dysfunction (Ccr < 30 ml/ min), similarly as in the study by van Hest et al. [19]. This may explain the lack of differences in MPA AUC0-4 h and Cmax values between groups with Ccr Arch Med Sci 1, February / 2012 95