Forty-two de novo renal transplant recipients receiving
mycophenolate mofetil and concomitant
cyclosporin (n = 32) or
tacrolimus (n = 10) participated in the study. Blood samples were taken on day 5 post-transplant for measurement of free and total concentrations of
mycophenolic acid,
mycophenolic acid glucuronide and relevant biochemistry. Associations between free fraction and biochemistry were investigated. Free and total 6-h area under the concentration-time curve (AUC0-6) of
mycophenolic acid was assessed relative to clinical outcomes in the first month post-transplant.
RESULTS: Kinetic variability of free and total
mycophenolic acid and its
glucuronide was greater in patients on
cyclosporin (12- to 18-fold variation) than on
tacrolimus (four- to fivefold) cotherapy.
Cyclosporin-treated patients also had significantly lower predose total
mycophenolic acid concentrations than
tacrolimus-treated patients (median 0.8 mg l(-1) and 1.6 mg l(-1), respectively, P = 0.002).
Mycophenolic acid glucuronide predose concentration correlated positively with
mycophenolic acid glucuronide AUC0-6 (r > 0.95).
Mycophenolic acid free fraction varied 11-fold, from 1.6% to 18.3%, whilst the
glucuronide free fraction varied threefold, from 17.4% to 54.1%.
Urea and
creatinine concentrations correlated positively (r > 0.46), whilst
albumin correlated negatively (r = -0.54) with free fraction of
mycophenolic acid. Similar relationships were found for the free fraction of
mycophenolic acid glucuronide.
Mycophenolic acid free fraction was on average 70% higher in patients with
albumin concentrations below a specified
albumin cut-off concentration of 31 g l(-1)[free fraction = 7 +/- 4% for lower
albumin and 4 +/- 3% for higher
albumin, respectively; P = 0.001; 95% confidence interval (CI) for the difference 1.9, 4.2]. Neither free nor total
mycophenolic acid AUC0-6 was related to rejection (P > 0.07). Free AUC0-6 was significantly higher in those patients with thrombocytopenic, leukopenic and/or infectious outcomes than in those without (mean +/- SD 1.9 +/- 0.3 mg h(-1) l(-1) and 1.1 +/- 0.1 mg h(-1) l(-1), P = 0.0043; 95% CI for the difference 0.3, 1.4).
CONCLUSIONS: