Interaction of Drugs of Dependence With Receptors
S.J. Mulé, Henry Brill in 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
Shufeng Zhou in 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a nonsedating H1 receptor antagonist, is used for the treatment of allergic conditions such as allergic rhinitis but withdrawn from the market because of fatal cardiotoxic-ity (e.g., torsade de pointes, brought about by QT prolongation and ventricular arrhythmias) (Honig et al. 1993).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 t-butyl hydroxylation activities were measured as described previously (Uehara et al., 2016b) in triplicate determinations unless otherwise specified. Briefly, the incubation mixtures consisted of tissue microsomes (0.10 mg/mL) or recombinant P450 protein (10 pmol equivalent), 100 mM potassium phosphate buffer (pH 7.4), and an NADPH-generating system (0.25 mM NADP+, 2.5 mM glucose 6-phosphate, and 1 unit/mL glucose-6-phosphate dehydrogenase), and 10 μM terfenadine (unless otherwise specified) in a final volume of 0.25 mL. The substrate concentration of 10 μM was chosen in relation to the literature Km value (Jones et al., 1998) and the value obtained in our preliminary studies performed for t-hydroxylation of terfenadine in liver and intestine microsomes and human and marmoset P450 2J2. For immunoinhibition studies, preimmune or anti-human P450 2J2, 3A4 and 4F12 antibodies (0–50 μL) were preincubated with liver or small intestine microsomes for 20 min. The reaction was carried out at 37 °C for 20 min and was terminated by the addition of ice-cold acetonitrile (1 mL). Samples were centrifuged at 10,000g for 10 min and the resulting supernatant was injected into Spherisorb-5-CN HPLC column (150 × 4.6 mm, 5 μm; Waters, Tokyo, Japan) in a HPLC system with elution by a mobile phase of 22.5% (v/v) acetonitrile and 22.5% (v/v) methanol in 6.6 mM ammonium acetate buffer (pH 4.0) at 1.3 mL/min at a column temperature of 40 °C. The metabolites were detected with at an excitation wavelength of 230 nm and an emission wavelength of 270 nm and a UV detector at 214 nm. The retention times of N-dealkylated azacyclonol, a secondary oxidative metabolite fexofenadine, t-butyl hydroxylated terfenadine and terfenadine were 3.5, 3.8, 4.6 and 5.7 min, respectively, under the present isocratic mobile phase conditions. The standard calibration curve indicated linearity with terfenadine t-butyl hydroxylated metabolite over the concentration ranges of 5–2000 ng/mL; the linearity for t-hydroxylation of terfenadine (10 μM) was assessed over ranges of 20 min incubation and 0.50 mg protein/mL in liver and intestine microsomes. The kinetic parameters were determined by nonlinear regression data analysis fit to the Michaelis–Menten (with or without substrate inhibition equations) using the Kaleida Graph program (Synergy Software, Reading, PA):
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