CRITICAL LIMIT OF BILIRUBIN CONCENTRATION FOR SELECTION OF HEALTHY-VOLUNTEERS TO PHASE-I STUDIES

10 % of young male healthy volunteers have a total bilirubin value ove r 20 mu mol/l; thus such a value appears not relevant as screening cut off point in clinical pharmacology. This study was intended to confir m if a 27 mu mol/l cut off point previously defined by the authors doe s not support a risk. This study dealt with 487 subjects who had toget her measurements of total bilirubin value and lab. tests of liver cyto lysis, cholestasis or hemolysis during the selection process. 48 subje cts (9.8 %) had a total bilirubin value over 20 mu mol/l. Correlation tests do not provide arguments of cytolysis, cholestasis or hemolysis and there was no argument in favor of Gilbert's syndrom. Out of 48 hyp erbilirubinemic subjects only 22 were included in clinical pharmacolog y studies. In more than 60 %, the total bilirubin value returned to no rmal spontaneously and in no case appeared a significant clinical, bio logical, pharmacokinetic or dynamic abnormality. Except a possible inc rease of slow acetylor frequency, the medical literature analysis does not show any relevant modification in metabolism, pharmacokinetics or pharmacodynamics until a 40 mu mol/l value of total bilirubin. Thus, the 27 mu mol/l value of total bilirubin previously proposed is confir med as a useful limit that does not lead to an additional risk.