Melatonin-based method offers simpler way to assess drug metabolism

A research group including Senior Lecturer Akitomo Yokokawa and Professor Hiromi Shibasaki at the Laboratory of Clinical Pharmacy and Experimental Therapeutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, announced on July 30 that they had developed an evaluation method for the activity of the drug-metabolizing enzyme CYP1A2 using the metabolism of melatonin, which is secreted as a sleep hormone in the body, as an indicator. Practical application as personalized medicine based on drug-metabolizing capacity is expected. The findings were published in the British Journal of Clinical Pharmacology.

CYP1A2 is a major hepatic drug-metabolizing enzyme involved in the metabolism of many pharmaceuticals, such as the schizophrenia therapeutic clozapine and the asthma therapeutic theophylline. Many genetic polymorphisms exist, and activity varies depending on these. It is known that its activity is affected by smoking, food, concomitant drugs, and other factors. Therefore, evaluating CYP1A2 activity prior to treatment is considered important for personalized drug therapy.

On the other hand, the method of ingesting caffeine currently used to investigate this activity at the research level required caffeine intake restriction before testing and caffeine ingestion as a test drug, not reaching clinical application. Therefore, this time, the research group focused on the fact that melatonin is metabolized into 6-hydroxymelatonin by CYP1A2. They established a method to evaluate CYP1A2 activity solely through blood and urine collection, without ingesting test drugs.

Targeting 18 healthy adults, they quantified urinary 6-hydroxymelatonin and blood melatonin and calculated the melatonin partial metabolic clearance by dividing the 2-hour urinary 6-hydroxymelatonin excretion amount by the area under the blood concentration-time curve of melatonin.

As a result, it significantly correlated with caffeine clearance and the paraxanthine/caffeine ratio, which are conventional methods. It was shown that CYP1A2 activity can be evaluated solely through blood and urine collection without ingesting test drugs.

Melatonin has a circadian rhythm where it is secreted in large amounts at night. Blood concentrations are high in the morning and decrease with the passage of time. As a result of comparing melatonin partial metabolic clearance between 10:00 a.m. to 12:00 p.m. and 2:00 p.m. to 4:00 p.m., it showed almost constant values in both time bands, confirming that evaluation is possible in either time band.

Yokokawa said, "For evaluating the activity of the drug-metabolizing enzyme CYP1A2, ingestion of test drugs was required until now. In this study, we consider it meaningful that we showed the possibility of evaluation utilizing melatonin existing inherently within the body. In the future, we wish to advance verification targeting patients, leading to applications in personalized drug therapy."

Journal Information
Publication: British Journal of Clinical Pharmacology
Title: Endogenous melatonin partial metabolic clearance as a potential endogenous marker of CYP1A2 activity
DOI: 10.1002/bcp.70589