Drugs online research references
Drug Metab Dispos. 1977 Mar-Apr;5(2):132-42.
Urinary metabolites of amitriptyline in the dog.
Hucker HB, Balletto AJ, Demetriades J, Arison BH, Zacchei AG.
Dogs excreted approximately 45% of an oral dose of 14C-amitriptyline (30 mg/kg) in the urine in 24 hr. Two new urinary metabolites of the drug were identified as dihydrodiol derivatives of amitriptyline and nortriptyline, respectively. The major metabolite in dog urine was 10-hydroxyamitriptyline, excreted mainly in conjugated form. Other metabolites were characterized as 10-hydroxynortriptyline, amitriptyline N-oxide, and nortriptyline. Together, these metabolites accounted for approximately 47% of the urinary radioactivity.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15805&dopt=Abstract
J Biol Chem. 1989 Jan 25;264(3):1508-15.
On the inhibition of the mitochondrial inner membrane anion uniporter by cationic amphiphiles and other drugs.
Beavis AD.
Department of Pharmacology, Medical College of Ohio, Toledo 43699.
Depleting the mitochondrial matrix of divalent cations with the ionophore A23187 activates a pH-sensitive, anion uniport pathway which can transport many anions normally regarded as impermeant (Beavis, A. D., and Garlid, K. D. (1987) J. Biol. Chem. 262, 15085-15093). Addition of valinomycin to respiring mitochondria can also induce the uptake of a wide variety of anions; however, the mechanism of anion transport during this "respiration-induced" swelling is less certain. In this paper, I demonstrate that both of these processes are inhibited by a variety of cationic amphiphiles including propranolol, quinine, amiodarone, imipramine and amitriptyline, and the benzodiazepine R05-4864. Although the IC50 values for the two processes are not equal, the ratio of IC50 values for the two processes appears to be the same for all drugs. Measurements of net transmembrane proton fluxes that occur during the assays reveal that respiration-induced swelling is associated with extensive proton ejection, the peak of which coincides with the maximum rate of anion transport. Moreover, from measurements of matrix buffering power, it is estimated that the matrix pH is 3 units more alkaline during respiration-induced swelling than during A23187-induced swelling. It is also shown that the IC50 for A23187-induced transport is pH-dependent in a manner consistent with modulation of drug binding by protonation of two sites. These findings allow the difference in IC50 values for the two types of assay to be explained by the pH dependence of the binding constant for the drug. Furthermore, the pH gradient generated during respiration-induced swelling is so large that the electrical component of the proton-motive force will be negligible. Thus, despite the fact that the mitochondria are "energized," rapid electrophoretic anion influx is possible. These data provide evidence that the transport of anions in these two types of assay occurs via the same pathway.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2492277&dopt=Abstract
J Pharm Sci. 1986 Feb;75(2):133-41.
13C NMR studies of the molecular flexibility of antidepressants.
Munro SL, Andrews PR, Craik DJ, Gale DJ.
The solution dynamics of a series of clinically potent antidepressants have been investigated by measuring 13C NMR relaxation parameters. Correlation times and internal motional rates were calculated from spin-lattice relaxation times and nuclear Overhauser effects for the protonated carbons in mianserin, imipramine-like antidepressants, and amitriptyline-like antidepressants. These data were interpreted in terms of overall molecular tumbling, internal rotations, and inherent flexibility of these structures. Of particular interest was the conformational variability of the tricyclic nucleus of the tricyclic antidepressants, where the data indicated a fivefold difference in mobility of the dimethylene bridge of imipramine-like antidepressants relative to amitriptyline-like compounds. The implications of such a difference in internal motions is discussed in relation to previous NMR studies and to the reported differences in pharmacological activity of these antidepressants.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3958921&dopt=Abstract
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