Published:Journal of Chromatographic Science,
ISSN 0021-9665 Volume
45, Number 10, November/December 2007, pp. 694-700
A LC–Electrospray Tandem MS Method for
the Analysis of Naltrexone in Canine Plasma Employing a Molecular
Model to Demonstrate the Absence of Internal Standard Deuterium
Isotope Effects
Sunil S. Iyer[1], Glen E. Kellogg[2], and H.
Thomas Karnes[1],
[1]Department of Pharmaceutics, School of Pharmacy, Virginia
Commonwealth University, Richmond, VA 23298-0533 and
[2]Department
of Medicinal Chemistry, School of Pharmacy & Institute for
Structural Biology and Drug Discovery, Virginia Commonwealth
University, Richmond, VA 23298-0540.
A simple and sensitive method is described for
the determination of naltrexone (NAL), an opioid antagonist,
in dog plasma. Sample processing involved a single step liquid–liquid
extraction, followed by evaporation of the supernatant, and reconstitution
of the residue prior to injection into the liquid chromatograph.
The peak height ratio of NAL to [15,15,16-2H] naltrexone (NAL-d3)
was used for quantitation. Observation of the chromatograms for
NAL and NAL-d3 revealed that the mean retention times of the
compounds were 1.32 and 1.31 min, respectively. The almost identical
retention times possibly accounted for the absence of matrix
effects influencing quantitation. Molecular mechanics calculations
using SYBYL software were carried out to qualitatively and quantitatively
assess analyte and isotopic internal standard stationary phase
interactions. Binding energy values of –10.22 and –10.26
kcal/mole were obtained for NAL and NAL-d3, respectively. These
data predict, semi-quantitatively, the absence of deuterium isotope
effects that may influence quantitation. Calibration curves were
linear from 10 pg/mL to 5014 pg/mL with a weighting factor of
1/x. Precision and accuracy and reverse predicted concentration
residuals were within 15%. The method has been used successfully
for the analysis of plasma samples from a pilot subcutaneous
implantation study in dog.
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