12 research outputs found
Pharmacokinetic properties of a novel inosine analog, 4′-cyano-2′-deoxyinosine, after oral administration in rats
<div><p>4′-cyano-2′-deoxyinosine (SK14-061a), a novel nucleoside analog based on inosine, has antiviral activity against the human immunodeficiency virus type 1 that has the ability to acquire resistance against many types of reverse transcriptase inhibitors based on nucleosides. The aim of this study was to investigate the pharmacokinetics studies after its oral administration to rats. For this purpose, we first developed and validated an analytical method for quantitatively determining SK14-061a levels in biological samples by a UPLC system interfaced with a TOF-MS system. A rapid, simple and selective method for the quantification of SK14-061a in biological samples was established using liquid chromatography mass spectrometry (LC-MS) with solid phase extraction. The pharmacokinetic properties of SK14-061a in rats after oral administration were then evaluated using this LC-MS method. SK14-061a was found to be relatively highly bioavailable, is rapidly absorbed from the intestinal tract, and is then mainly distributed to the liver and then ultimately excreted via the urine in an unchanged form. Furthermore, the simultaneous administration of SK14-061a with the nucleoside analog, entecavir, led to a significant alteration in the pharmacokinetics of SK14-061a. These results suggest that the SK14-061a has favorable pharmacokinetic properties with a high bioavailability with the potential for use in oral pharmaceutical formulations, but drug-drug interactions should also be considered.</p></div
Pharmacokinetic parameters of SK14-061a after intravenous and oral administration of a dose of 1 mg/kg in rats.
<p>Pharmacokinetic parameters of SK14-061a after intravenous and oral administration of a dose of 1 mg/kg in rats.</p
Time course for the plasma concentration of SK14-061a after oral administration at a dose of 1 mg/kg in rats.
Venous blood samples were collected at 15 min, 45 min, 90 min, 3, 4.5, 6 and 9 hr after oral administration. The SK14-061a concentrations in plasma were measured by LC-MS combined with the SPE method. The values are the mean ± SD. (n = 4).</p
Intra- and inter-day accuracy and precision for SK14-061a in plasma.
<p>Intra- and inter-day accuracy and precision for SK14-061a in plasma.</p
Pharmacokinetic parameters of SK14-061a and ETV after the oral co-administration of SK14-061a and ETV at a dose of 1 mg/kg in rats.
<p>Pharmacokinetic parameters of SK14-061a and ETV after the oral co-administration of SK14-061a and ETV at a dose of 1 mg/kg in rats.</p
LC-MS chromatograms of (A) SK14-061a spiked with water, (B) SK14-061a spiked with plasma after a methanol treatment, (C) SK14-061a spiked with plasma after an acetonitrile treatment, (D) blank plasma after SPE treatment, and (E) SK14-061a spiked with plasma after SPE treatment.
<p>All SK14-061a samples contained 500 ng/mL in concentration before either reverse liquid-liquid extraction or SPE. The SK14-061a were detected by the LC-MS as described in the Materials and Methods section.</p
(A) Time course for the plasma concentration of ETV after an oral administration of ETV alone (closed circle) or combination with SK14-061a (open circle) at doses of 1 mg/kg in rats. (B) Time course for the concentration of SK14-061a in plasma after the oral administration of SK14-061a alone (closed circle) or combination with ETV (open circle) at doses of 1 mg/kg in rats.
<p>Venous blood samples were collected at 15 min, 45 min, 90 min, 3, 6 and 9 hr after administration. The SK14-061a and ETV concentrations in plasma were measured using LC-MS with the SPE method. The data for SK14-061a alone are quoted from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198636#pone.0198636.g003" target="_blank">Fig 3</a>. The values are the mean ± SD. (n = 4).</p
LC-MS chromatograms of SK14-061a in urine.
<p>Urine samples were collected in a metabolic cage and were pretreated on an SPE column (Waters Oasis MCX 96 well plate) for extracting SK14-061a as described in the Materials and Methods section.</p
Chemical structure of 4′-CN-2′-deoxyinosine (SK14-061a).
<p>Chemical structure of 4′-CN-2′-deoxyinosine (SK14-061a).</p
The tissue distribution to (A) liver and (B) kidney of SK14-061a at 1, 3 and 9 hr after oral administration at a dose of 1 mg/kg in rats.
<p>The values are the mean ± SD. (n = 4).</p