Myrtucommulone from Myrtus communis: Metabolism, Permeability, and Systemic Exposure in Rats

Abstract

Nonsteroidal anti-inflammatory drug intake is associated with a high prevalence of gastrointestinal side effects, and severe cardiovascular adverse reactions challenged the initial enthusiasm in cyclooxygenase-2 inhibitors. Recently, it was shown that myrtucommulone, the active ingredient of the Mediterranean shrub Myrtus communis, dually and potently inhibits microsomal prostaglandin E₂ synthase-1 and 5-lipoxygenase, suggesting a substantial anti-inflammatory potential. However, one of the most important prerequisites for the anti-inflammatory effects in vivo is sufficient bioavailability of myrtucommulone. Therefore, the present study was aimed to determine the permeability and metabolic stability in vitro as well as the systemic exposure of myrtucommulone in rats. Permeation studies in the Caco-2 model revealed apparent permeability coefficient values of 35.9 · 10⁻⁶ cm/s at 37 °C in the apical to basolateral direction, indicating a high absorption of myrtucommulone. In a pilot rat study, average plasma levels of 258.67 ng/mL were reached 1 h after oral administration of 4 mg/kg myrtucommulone. We found that myrtucommulone undergoes extensive phase I metabolism in human and rat liver microsomes, yielding hydroxylated and bihydroxylated as well as demethylated metabolites. Physiologically-based pharmacokinetic modeling of myrtucommulone in the rat revealed rapid and extensive distribution of myrtucommulone in target tissues including plasma, skin, muscle, and brain. As the development of selective microsomal prostaglandin E₂ synthase-1 inhibitors represents an interesting alternative strategy to traditional nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for the treatment of chronic inflammation, the present study encourages further detailed pharmacokinetic investigations on myrtucommulone.

Review of Pharmacological Effects ofMyrtus communisL. and its Active Constituents

“…According to these data, myrtle could be considered as an alternative agent for the treatment of chronic inflammation without the typical side effects of Coxibs and non‐steroidal antiinflammatory drugs (Gerbeth et al ., ).…”

Antioxidant Activity of Myrtus communis L. and Myrtus nivellei Batt. & Trab. Extracts: A Brief Review

“…The mechanisms involved in the anti-inflammatory activity of myrtucommulone isolated from myrtle leaves have been cleared by diverse research teams as aforementioned; nevertheless there is no information about its bioavailability. Gerbeth et al [ 155 ] proposed to study the metabolic stability of that acylphloroglucinol, obtained by synthesis, using rat and human liver microsomes and its oral availability in a pilot rat study. The study started by using Caco-2 cells and the results showed a high absorption of myrtucommulone.…”

“…The study started by using Caco-2 cells and the results showed a high absorption of myrtucommulone. In rat model, the authors [ 155 ] reported that after 1 h of administrating 4 mg/kg myrtucommulone, an average plasma level of 258.67 ng/mL was observed. Physiologically-based pharmacokinetic modelling of myrtucommulone in the rat, it was observed that it was rapid and extensively distributed by plasma, skin, muscle, and brain.…”

“…Physiologically-based pharmacokinetic modelling of myrtucommulone in the rat, it was observed that it was rapid and extensively distributed by plasma, skin, muscle, and brain. Moreover, myrtucommulone undergoes phase I biotransformation in human and rat liver microsomes, resulting hydroxylated and demethylated metabolites [ 155 ].…”

Myrtucommulone-A Induces both Extrinsic and Intrinsic Apoptotic Pathways in Cancer Cells

“…Myrtucommulone (MC) is an oligomeric nonprenylated acylphloroglucinols mainly obtained from Myrtus communis . Myrtucommulone or active ingredients (MC‐A) has not been used yet in clinics for any disease.…”