Calculation of Human Melatonin Partial Metabolic Clearance in Healthy Adult Volunteers for Investigation of a Novel in Vivo CYP1A2 Phenotyping Method: A Pilot Study

The method of administering caffeine as a probe to evaluate the phenotypic activity of the CYP1A2, has not yet been applied clinically. In contrast, if endogenous melatonin (MEL) metabolism can be used to assess CYP1A2 activity, it could be a simple method that does not require substance administration. The study aim was to calculate the MEL partial metabolic clearance (CL_m(MEL)) from plasma MEL and its urinary metabolites and to test the potential of this approach as a novel CYP1A2 phenotyping method. Nine subjects were included in the study; 3 had 6 blood and 4 urine samples collected between 10:00 and 18:00 (collectively, the intraday sample). Nine subjects had 3 blood samples and 2-h urine samples collected between 10:00 and 12:00 once a week for 3 weeks (interday sample). The CL_m(MEL) was calculated from the plasma area under the curve (AUC) of MEL (AUC_MEL) and urinary MEL metabolites excretion (X_6MEL). Among the intraday samples, the AUC_MEL ranged from 6.45-13.17 pmol·h/L and X_6MEL ranged from 0.204-0.899 nmol/2 h, showing a decrease in concentration over time. In contrast, the CL_m(MEL) ranged from 30.52-69.57 L/h (within-individual percent relative standard deviation: 9.2-20.1%), showing no time-dependent variation. Large interindividual variability was observed in AUC_MEL and X_6MEL in the interday sample, but CL_m(MEL) showed small interindividual variabilities. The CL_m(MEL) was 1.8-fold higher for smokers than for nonsmokers. The results obtained in this study may be valuable in future studies of evaluating novel CYP1A2 phenotyping method.