The effect of CYP2C19 substrate on the metabolism of melatonin in the elderly: A randomized, double-blind, placebo-controlled study
Abstract
The metabolism of melatonin to 6-sulphatoxymelatonin (aMT6S) and N-acetylserotonin (NAS) is catalyzed by cytochrome-P450 (CYP) isozymes CYP1A2 and CYP2C19 respectively. We studied the in vivo effect of CYP2C19 substrate (citalopram, omepratzole, or lansopratzole) on the metabolism of endogenous and exogenous melatonin by measuring the excretion of urinary aMT6S, the main metabolite of melatonin, and a reliable estimate of plasma melatonin in 15 insomniac psychogeriatric inpatients. The effect of melatonin treatment on sleep parameters was also assessed. The patients with or without CYP2C19 substrate were treated for 21 days randomly in a double-blind manner with placebo or 2 mg exogenous melatonin orally. aMT6S excretions were measured radioimmunologically from night urine at baseline (day 0), on day 21, and one day after the treatment was discontinued (day 22). Sleep parameters were assessed using the Sleep Assessment Scale and the Sleep Quality Scale. In the control patients receiving only melatonin, aMT6S excretion increased 72-fold and returned to baseline on day 22. In the patients receiving melatonin + CYP2C19 substrate, aMT6S excretion increased 156-fold and was, on day 22, still 6.4-fold higher than at baseline (p = 0.04). The 22/0 day aMT6S excretion ratio was 10-fold higher in the patients treated with melatonin + CYP2C19 substrate when compared with that in the subjects treated with placebo + CYP2C19 substrate (p = 0.02). CYP2C19 substrate did not affect the metabolism of endogenous melatonin. The sleep parameters in the patients on melatonin treatment did not differ from those in the patients treated with placebo. In conclusion, it may be inferred that CYP2C19 substrate slows the metabolism of exogenous melatonin and increases its bioavailability, as shown by the augmented excretion of aMT6S, probably by inhibiting the conversion of melatonin to NAS via CYP2C19 isozyme. Melatonin therapy may not affect the sleep parameters in our psychogeriatric inpatients.
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The majority of melatonin is metabolized through CYP1A2, with lesser metabolic activity through CYP1A1, CYP1B1, and CYP2C19.
“Earlier research has identified that the majority of melatonin is metabolized through cytochrome (CYP) 1A2 [292,301], with lesser metabolic activity through CYP1A1, CYP1B1, and CYP2C19 [292,302].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [302]
Medications that affect CYP1A2, CYP1A1, CYP1B1, and CYP2C19 enzymatic pathways will influence melatonin metabolism.
“Therefore, medications that affect these enzymatic pathways will influence melatonin metabolism.”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [302]
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“Urine aMT6s concentration was determined by direct radioimmunoassay using a commercial kit (Stockgrand, Surrey, UK) as previously described [ 19 ].”
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“Additionally, NAS is a minor metabolite produced via CYP2C19 and 1A2 in humans (Ma et al., 2005; Huuhka et al., 2006).”
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- Authors
- Huuhka, K., Riutta, A., Haataja, R., Ylitalo, P., & Leinonen, E.
- Affiliations
- Tampere University Hospital (FI)
- ORCID
- Riutta, A.
- Venue
- Methods and Findings in Experimental and Clinical Pharmacology
- Publisher
- Portico
- Published
- 2006
- Volume
- 28
- Issue
- 7
- Pages
- 447
- ISSN
- 0379-0355 (ISSN-L)
- 2013-0155
- OpenAlex
- W2007831337
- Cited by
- 16
- References
- 0
- Citations by year
- 2026: 1 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 1 · 2018: 1 · 2016: 3 · 2015: 1 · 2014: 1 · 2013: 1
- FWCI
- 0.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Methods and Findings in Experimental and Clinical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Keywords
- melatonin metabolism, 6-sulfatoxymelatonin, N-acetylserotonin, cytochrome P450 inhibition, citalopram, omeprazole, lansoprazole, psychogeriatric patients, sleep quality, drug-drug interactions, urinary melatonin metabolites
- MeSH terms
- Aged, Aged, 80 and over, Anticonvulsants, Aryl Hydrocarbon Hydroxylases, Mental Disorders, Double-Blind Method, Drug Therapy, Combination, Enzyme Inhibitors, Female, Humans, Mixed Function Oxygenases, Male, Melatonin, Omeprazole, Sleep Wake Disorders, Time Factors, Citalopram, Treatment Outcome, Selective Serotonin Reuptake Inhibitors, Antidepressive Agents, Second-Generation, 2-Pyridinylmethylsulfinylbenzimidazoles, Lansoprazole, Cytochrome P-450 CYP2C19
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