RELATIONSHIP BETWEEN APPARENT TOTAL-BODY CLEARANCE OF CYCLOSPORINE-A AND ITS ERYTHROCYTE-TO-PLASMA DISTRIBUTION RATIO IN RENAL-TRANSPLANT PATIENTS

To establish an optimal method for determining a cyclosporin A (CYA) r egimen based on physiological changes that occur during immunosuppress ive therapy, the relationship between apparent CyA body clearance (CL/ f) and the CyA erythrocyte-to-plasma distribution ratio (CyA-EP) was e xamined using clinical time courses obtained during routine monitoring . The CyA-EP, which was calculated by a multiple regression formula us ing routine data, was increased during renal dysfunction involving the normal recovery phase after transplantation, during nephrotoxicity, d uring acute tubular necrosis, and during acute renal rejection. CyA to tal body clearance (CL(t)), calculated by multiplying CL/f and convert ed bioavailability, f(c) (which is equal to 0.009 x LD, where LD repre sents the CyA level in blood per dose ratio), showed hyperbolic decay with increasing CyA-EP (the mean CL(t) was defined as follows: CL(t)=0 .937/CyA-EP), whereas f(c) showed exponential decay with increasing Cy A-EP (the mean f(c) was defined as follows: f(c)=0.593 x exp(-0.155 x CyA-EP)). These findings suggest that total CyA body clearance and its bioavailability were suppressed during the renal dysfunction phase. H ence, the mean CL/f as a function of the CyA-EP was given by the follo wing equation: CL/f=1.390 x exp(0.204 x CyA-EP)/CyA-EP. Since the CyA- EP reflects a patient's disease state and alterations in the CyA pharm acokinetic profile, these model formulae should provide an adequate me thod for determining a CyA dosage regimen for several disease states a fter renal transplantation.