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T N Thompson

Publications and source records attributed to T N Thompson.

26 records · Page 2Linked to original sources
PubMed1983

Depletion of hepatic uridine diphosphoglucuronic acid decreases the biliary excretion of drugs.

Hepatic levels of uridine diphosphoglucuronic acid (UDPGA) in rats decreased substantially (greater than 80%) 40 min after galactosamine (GAL) (600 mg/kg i.p.) or after 1 hr of diethyl ether (DE) narcosis. Biliary excretion of several cholephils requiring glucuronidation before excretion was reduced by GAL 76, 62, 92, 90 and 97% for bilirubin, diethylstilbestrol, iopanoic acid, phenolphthalein and valproic acid, respectively. GAL treatment caused delayed plasma clearances of the parent compounds and reductions in plasma concentrations and biliary excretions of glucuronide conjugates. The degree of this reduction was related to the maximal excretion rate of the individual compounds. For phenolphthalein glucuronide and phenol-3,6-dibromphthalein disulfonate, which do not undergo conjugation, GAL had no effect on their biliary excretion. DE-induced UDPGA depletion had no effect on phenolphthalein glucuronide excretion but reduced that of phenol-3,6-dibromphthalein disulfonate 25%. DE did not affect the plasma elimination or biliary secretion of phenolphthalein. Of the other cholephils requiring conjugation, DE reduced the excretion of bilirubin, diethylstilbestrol, iopanoic acid and valproic acid by 41, 29, 76 and 28%, respectively. DE decreased the plasma elimination of the parent compounds and the appearance of the conjugates in both plasma and bile. Reduction of glucuronide excretion into bile was less pronounced at higher doses of the cholephilic anions. Neither treatment reduced in vitro hepatic UDP-glucuronosyltransferase activity toward these substrates or substantially altered extrahepatic UDPGA concentrations. Thus, both GAL and DE decreased UDPGA to similar concentrations, but the biliary excretion of compounds requiring glucuronidation before secretion was depressed to a greater extent by GAL.

Animals↗
PubMed1978

Actinomycin D-deoxynucleotide interactions: binding isotherms at the benzenoid and quinoid portions of the drug.

Titrations of actinomycin D (AMD) with dG and with dG-dC were monitored by circular dichroism at 380 nm and 470 nm. These wavelengths are sensitive predominantly to nucleotide binding processes at the benzenoid and quinoid portions, respectively, of the phenoxazone ring of the drug chromophore [Auer, H.E., Pawlowski-Konopnicki, B.E., Chiao, Y.C.C. & Krugh, T.R. (1978), Biopolymers, 17, 1891-1911.]. The temperature dependence of these isotherms was analyzed by the van't Hoff equation to obtain values for the enthalpy and entropy changes. For dG these are about -11 kcal mol-1 and -20 cal mol-1 deg-1, respectively, for complex formation at both the benzenoid and quinoid sites (1 cal = 4.184 J). The enthalpy and entropy changes for complex formation with dG-dC remain unchanged at the benzenoid site, but both values are more negative at the quinoid site. These results indicate that the additional process of binding C in the intercalated AMD-(dG-dC)2 complex, with respect to the simply stacked AMD-dG2 complex, has distinctive properties at the two sites, reflecting their structural differences. The ability to resolve binding processes at the two sites by circular dichroism has permitted us to suggest assignments for the two 31P magnetic resonance lines from the phosphodiester groups observed in the AMD-(pdG-dC)2 complex.

Binding Sites↗
PubMedDate not supplied

Evaluation of the BBMEC model for screening the CNS permeability of drugs.

Combinatorial synthesis and high-throughput pharmacology screening have greatly increased compound throughput in modern drug-discovery programs. For CNS drugs, it is also important to determine permeability to the blood--brain barrier. Yet, given the increased pace of discovery, it difficult to conduct this screen in a timely fashion. In this presentation, we describe several improvements to an existing CNS permeability screen, the bovine brain microvessel endothelial cell (BBMEC) model. By implementation of these incremental process improvements, we have achieved a robust, facile screen for determination of CNS permeability of multiple compounds.

Animals↗