Orally given melatonin may serve as a probe drug for cytochrome P450 1A2 activity in vivo: A pilot study

Background Melatonin is a hormone that is metabolized by cytochrome P450 (CYP) 1A2 to its main primary metabolite 6‐hydroxymelatonin. We therefore evaluated the utility of oral melatonin as a marker of hepatic CYP1A2 activity. Methods Twenty‐five milligrams of melatonin was given at 9:30 am to 12 healthy Swedish volunteers, who had previously been phenotyped for CYP1A2 with caffeine. Melatonin and conjugated 6‐hydroxymelatonin were analyzed by liquid chromatography–mass spectrometry in blood samples taken between 0.5 and 6.5 hours after drug intake. Serum concentrations of melatonin and conjugated 6‐hydroxymelatonin, or their ratio at different time points, and the apparent melatonin clearance were tested for correlation with caffeine clearance. Results We found a significant correlation between apparent clearance of melatonin and caffeine clearance with a Spearman rank correlation coefficient (Rs) of 0.75 ( P = .005). The melatonin concentration 1.5 hours after administration also closely correlated with the caffeine clearance (Rs = −0.62; P = .03). Inclusion of conjugated 6‐hydroxymelatonin gave no closer correlations. Conclusion Melatonin might be developed as an alternative to caffeine as a probe drug for CYP1A2 phenotyping. Clinical Pharmacology & Therapeutics (2001) 70 , 10–16; doi: 10.1067/mcp.2001.116512