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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Mequitazine is a potent, nonsedative, and long-acting histamine H1 receptor antagonist proven to be a better therapeutic drug than other conventional antihistamines (Fujimura et al. 1981). The oxidative metabolism of mequitazine is extensively studied in rats and dogs (Uzan et al. 1976a,b). The major metabolic routes of mequitazine in rats are the aromatic hydroxylation of the phenothiazine structure and S-oxidation and N-oxidation of a side chain (Hojo et al. 1981). In human liver microsomes, two metabolites, M1 (S-oxide) and M2 (hydroxylated metabolite), are formed by CYP2D6 (Figure 3.79) (Nakamura et al. 1998). Microsomes from human B-lymphoblastoid cells expressing CYP2D6 efficiently metabolize mequitazine to the hydroxylated and S-oxidized metabolites (Nakamura et al. 1998).
Second-generation antihistamines: a study of poisoning in children
Published in Clinical Toxicology, 2020
Eva Verdu, Ingrid Blanc-Brisset, Géraldine Meyer, Gaël Le Roux, Chloé Bruneau, Marie Deguigne
These substances are competitive, reversible H1-receptor antagonists. They relieve the effects of histamine, which is produced by mast cells following an allergic reaction or a non-allergic release of histamines. The first H1 antihistamines, known as first-generation, came onto the market in the 1940s [6]. These first-generation substances, still on the market today, have weak selectivity for H1 receptors and are able to pass the blood-brain barrier (BBB), which mainly leads to sedative and anticholinergic effects, but also to α-adrenergic receptor and serotonin effects. Mequitazine is a first-generation antihistamine in the phenothiazine family marketed in several countries in Europe, Africa and South America. In France, mequitazine is frequently prescribed (>1 million medical prescriptions in 2005 and 837,000 in 2015 including 30% for the treatment of chickenpox) [7]. In 1981, the second generation of anti-H1 antihistamines, with better selectivity for H1 receptors and less ability to pass the BBB, was commercialised. However, in 1986, reports on the cardiotoxicity of these new substances, terfenadine and astemizole, began to appear, resulting in their removal from the market in 1999. This encouraged the development of research into the mechanisms of cardiotoxicity in medications and subsequently, other antihistamines that were believed to be less cardiotoxic were marketed [6,8]. However, the effects of an overdose, including cardiotoxicity, are not well known and literature on the subject is sparse, notably with regard to children.