Correction for non-ideal tracer pharmacokinetic disposition by disposition decomposition analysis (DDA).
OBJECTIVE
Pharmacokinetic (PK) studies assume that the tracer's PK is equivalent to the parent compound. This assumption is often violated. The aim of this work is to present a method enabling the ideal tracer PK, i.e. the PK of the parent compound, to be predicted from the non-ideal tracer.


METHODS
The procedure uses a disposition decomposition-recomposition (DDR) that assumes that the labeling mainly changes the elimination kinetics while the distribution kinetics is not significantly affected. In the DDR procedure an elimination rate constant correction factor (kCOR) is determined from a simultaneously fitting to plasma concentration data resulting from an i.v. injection of both the tracer and the parent compound. The correction factor is subsequently used to predict the ideal tracer PK behavior from the disposition function (i.v. bolus response) of the non ideal tracer.


RESULTS
The DDR method when applied to plasma level data of erythropoietin (r-HuEPO) and its iodinated tracer (125I-r-HuEPO) from a high (4000U/kg) and a low (400U/kg) dosing of r-HuEPO in newborn lambs (n=13) resulted in excellent agreements in the elimination rate corrected dispositions in all cases (r=0.995, SD=0.0095). The correction factor did not show a dose dependence (p > 0.05). The correction factors were all larger than 1 (kCOR=1.94, SD=0.519) consistent with a reduction in the EPO elimination by the iodination labeling.


CONCLUSIONS
The DDR tracer correction methodology produces a better differentiation of the PK of endogenously produced compounds by correcting for the non-ideal PK behavior of chemically produced tracers.
The College of Pharmacy, Department of Pharmaceutics, The University of Iowa, Iowa City 52242, USA. veng@uiowa.edu
P
P
Veng-Pedersen
S S
SS
Hong
J A
JA
Widness
R L
RL
Schmidt
D000818:Animals; D004355:Drug Stability; D004921:Erythropoietin / Q000493:pharmacokinetics; D005069:Evaluation Studies as Topic; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008962:Models, Theoretical; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D012756:Sheep
D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D011994:Recombinant Proteins; D004921:Erythropoietin