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Interaction of Drugs of Dependence With Receptors
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
Results from a number of studies have suggested that although mescaline may have a single type of receptor interaction, nevertheless it produces multiple effects. This is apparent from the variety of agents which block its pharmacological effects, such as atropine, azacyclonol, pheno-thiazines, and amytal.62 This relative non-specificity is unfortunate since mescaline often is used as the reference compound in studies of other psychotomimetic drugs. If mescaline has several different areas in which it is acting pharmacologically, it would probably be more advantageous when studying SAR to relate potency to the brain concentrations of the drugs rather than to their dosages. This point will be discussed further in the section on amphetamines, where STP is compared with mescaline.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Terfenadine, a nonsedating H1 receptor antagonist, is used for the treatment of allergic conditions such as allergic rhinitis but withdrawn from the market because of fatal cardiotoxic-ity (e.g., torsade de pointes, brought about by QT prolongation and ventricular arrhythmias) (Honig et al. 1993). After oral administration, terfenadine is well absorbed and undergoes extensive first-pass metabolism in humans. It is mainly metabolized by N-dealkylation to azacyclonol and hydroxylation of the t-butyl group to hydroxyterfenadine (Figure 3.81) (Garteiz et al. 1982). Hydroxyterfenadine is further oxidized to the corresponding carboxylic acid (carboxyterfenadine; marketed as fexofenadine), which is the biologically active antihistamine (von Moltke et al. 1994). CYP3A4 is the principal enzyme responsible for the N-dealkylation of terfenadine to form azacyclonol and hydroxyterfenadine (Yun et al. 1993). As a lipophilic arylalkylamine, terfenadine is considered to interact with CYP2D6, either as a substrate or as an inhibitor (Smith and Jones 1992). Substrate overlays indicate that terfenadine contains a basic nitrogen atom and the site of metabolism in a spatial orientation would facilitate binding to CYP2D6, by comparison with dextromethorphan. When terfenadine is docked into a homology model of CYP2D6 with the t-butyl group oriented close to the heme to allow metabolism, the basic nitrogen is able to interact with Asp301, an amino acid residue critical for the ion-pair interaction (Jones et al. 1998). Amino acids that appeared to be in direct contact with the diphenyl-4-piperidinemethanol group in this model included Ala300, Leu248, Phe247, Leu208, Gly113, and Pro114 (Jones et al. 1998). Terfenadine is metabolized to hydroxyterfenadine and azacyclonol mainly by CYP3A4 and 2D6 in human liver microsomes (Jones et al. 1998). In recombinant enzymes, only CYP2D6 and 3A4 result in hydroxyterfenadine. In addition to hydroxyterfenadine, the recombinant CYP3A4 also forms significant amounts of azacyclonol. Only recombinant CYP3A4, but not 2D6, metabolizes hydroxyterfenadine to azacyclonol and carboxyterfenadine (Jones et al. 1998).
Terfenadine t-butyl hydroxylation catalyzed by human and marmoset cytochrome P450 3A and 4F enzymes in livers and small intestines
Published in Xenobiotica, 2018
Shotaro Uehara, Yukako Yuki, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Terfenadine oxidation activities by recombinant human and marmoset P450s were further investigated (Figure 5). Formation of t-butyl hydroxylated terfenadine and a secondary oxidative metabolite fexofenadine was seen at a substrate concentration of 10 μM terfenadine by human and marmoset recombinant P450 2J2, 3A4 and 4F12 enzymes under the present conditions. Slow N-dealkylated azacyclonol formation by human P450 3A4/5 and marmoset P450 3A90 was also seen. Kinetic analyses for t-butyl hydroxylation activities by recombinant human and marmoset P450 enzymes were carried out (Figure 6). Kinetic parameters calculated using Michaelis–Menten equation with and without substrate inhibition constants are summarized in Table 1. Human P450 2J2 and 4F12 and marmoset P450 3A90 and 4F12 showed high catalytic activities at low substrate concentrations. Under the present conditions, human and marmoset P450 2J2 enzymes showed low Km values without any substrate inhibition constants (<400 μM). The other human and marmoset P450 enzymes tested in the kinetic studies showed terfenadine t-butyl hydroxylation activities with apparent substrate inhibition constants (Ks) of 84–144 μM (under 26–76 μM of Km values, Table 1), in similar manners to liver and intestine microsomes as shown in Figure 2.