EFFECT OF REPEATED DOSING ON THE PHARMACOKINETICS OF ORAL FLUCONAZOLEIN BONE-MARROW TRANSPLANT PATIENTS

We examined the pharmacokinetics of fluconazole in II bone marrow tran splant patients after multiple oral daily dose of 200 mg of this drug. Blood was sampled at different intervals on day 1, day 13, and day 27 . No dose was given on day 2, day 14, and day 28 to allow the concentr ation-time data to be collected over 48 hours. The 24 hour urine was a lso collected, and fluconazole was analyzed in both plasma and urine b y a high performance liquid chromatography. The plasma concentration-t ime data were best described by the one-compartment model with first-o rder absorption. The overall inter-day change and the difference betwe en day 1 and day 27 in the rate constant for absorption (k(a)), peak p lasma concentration (C-max), trough plasma concentration (C-min), time -to-peak (t(max)), area-under-the-curve 0-24 (AUC(0-24)), rate constan t for elimination (k(e)), mean residence time after oral administratio n (MRTor), and fraction of the dose excreted unchanged in urine 24 hou rs (fu(24)) were significant (P less than or equal to 0.0029 and P les s than or equal to 0.01, respectively). However, the difference betwee n day 1 and day 13 wets significant (P less than or equal to 0.05) onl y in k(a), t(max), C-max, C-min, and AUC(0-24), and between day 13 and day 27 was significant (P less than or equal to 0.05) only in k(a), C -min, k(e), and MRTor. There was no significant inter-day change in th e renal clearance. The significant (P less than or equal to 0.05) incr eases in C-max, C-min, and AUC(0-24), after the dose given on day 13 a s compared with day 1, and in C-min, on day 27 as compared with day 13 indicate that, in contrast to volunteers, the steady state condition was not reached on day 13 and possibly not on day 27 in these patients . This perhaps should be taken into account when prescribing fluconazo le to seriously ill patients.