Pharmacokinetics of HZ08 in rats by liquid chromatography–tandem mass spectrometry
A selective and sensitive liquid chromatographic method coupled with ion spray tandem mass spectrometry detection (LC–MS/MS) was developed for the determination and pharmacokinetic study of N-cyano-1-[(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxy- N′-octyl-2(1H)-isoquinoline-carboximidamide...
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Published in | Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Vol. 856; no. 1; pp. 29 - 34 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Amsterdam
Elsevier B.V
01.09.2007
Elsevier Science |
Subjects | |
Online Access | Get full text |
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Summary: | A selective and sensitive liquid chromatographic method coupled with ion spray tandem mass spectrometry detection (LC–MS/MS) was developed for the determination and pharmacokinetic study of
N-cyano-1-[(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxy-
N′-octyl-2(1H)-isoquinoline-carboximidamide (HZ08, a candidate reversing agent for multidrug resistance of cancer) liposome injection in rat plasma. The analyte was extracted from plasma using liquid–liquid extraction by methyl
tert-butyl ether with drotaverine as internal standard. The chromatographic separation was performed on a Kromasil-C18 column (150
mm
×
4.6
mm, i.d., 5
μm) with gradient elution. The tandem mass detection was made with electrospray ionization in positive ion selected reaction monitoring mode with argon collision-induced dissociation. The ion transitions were
m/
z 523.1 to 342.1 for HZ08 at 27
eV and
m/
z 398.1 to 326.1 at 35
eV for the internal standard, respectively. The determination was validated to be accurate and precise for the analysis in the concentration range of 5–10,000
ng/ml for HZ08 with the lower limit of detection (LOD) being 1
ng/ml, when 0.1
ml of rat plasma sample was processed. The main pharmacokinetic parameters found for HZ08 after intravenous (i.v.) administration of its liposome injection at doses of 2, 4 and 8
mg/kg were as follows:
C
max (4511
±
681), (5553
±
1600) and (6444
±
950)
ng/ml,
T
max (0.033
±
0), (0.056
±
0.048) and (0.033
±
0)
h,
t
1/2 (1.75
±
0.19), (1.63
±
0.12) and (1.56
±
0.18) h, AUC
0–6 (899
±
112), (1238
±
190) and (1707
±
307)
h
ng/ml, AUC
0-∞ (917
±
110), (1256
±
189) and (1723
±
306)
h
ng/ml, MRT (1.14
±
0.21), (1.01
±
0.13) and (1.16
±
0.17)
h, CL (2.90
±
0.15), (3.01
±
0.74) and (4.11
±
0.59)
l/h/kg, respectively. The plasma concentration–time profiles of HZ08 were best fitted with two-compartment models. Linear pharmacokinetics was found for HZ08 in rats after intravenous administration of the liposome injection. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1570-0232 1873-376X |
DOI: | 10.1016/j.jchromb.2007.05.013 |