Pharmacokinetics of kadsurenone and its interaction with cyclosporin A in rats using a combined HPLC and microdialysis system.
Kadsurenone is a neolignan with specific antagonistic activity of platelet-activating factor, and is derived from the stems of Piper kadsura. To investigate the mechanism of hepatobiliary excretion of kadsurenone and its association with P-glycoprotein (P-gp), and to explore whether the hepatobiliary excretion of kadsurenone was associated with P-gp, a microdialysis system coupled with HPLC was developed to measure free-form kadsurenone in rat blood and bile. This study design was parallel in the following groups: six rats received kadsurenone alone (20 and 30 mg/kg, i.v.) as control group and the treated-group rats were co-administered with kadsurenone and CsA; P-gp inhibitor. The microdialysis probes were respectively inserted into the jugular vein toward right atrium and bile duct of male Sprague-Dawley rats for blood and bile sampling. CsA (20mg/kg) was administered 10 min prior to kadsurenone administration through the femoral vein and the collected samples were analyzed by a HPLC system. The analytes were separated by a C18 column (150 x 4.6 mm I.D., 5 microm) with a mobile phase of acetonitrile-water (50:50, v/v) at a flow-rate of 1 mL/min. The UV detection wavelength was set 235 nm. The calibration curve was linear over the concentration range of 0.05-10 microg/mL with the coefficient of determination of 0.997. The inter- and intra-assay accuracy and precision of the method ranged from -9.53% to 6.75%. The limit of detection and the limit of quantification were 0.01 and 0.05 microg/mL, respectively. The hepatobiliary excretion ratio of kadsurenone was defined by dividing the values of the area under the drug concentration curve (AUC) for bile and blood (AUC(bile)/AUC(blood)). The results indicated that the hepatobiliary excretion ratio of kadsurenone on the CsA treated-group was 1.2+/-0.1, which was not significantly different from the group of kadsurenone alone (1.3+/-0.2). This fact indicates that kadsurenone went through hepatobiliary excretion but might not be regulated by P-gp.
Huang
Shu-Pei
SP
Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Lin
Lie-Chwen
LC
Wu
Yu-Tse
YT
Tsai
Tung-Hu
TH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001572:Benzofurans / Q000032:analysis / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D004365:Drugs, Chinese Herbal / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics*; D017705:Lignans / Q000032:analysis / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D017551:Microdialysis; D031701:Piper / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001572:Benzofurans; D004365:Drugs, Chinese Herbal; D017705:Lignans; D016572:Cyclosporine; C044540:kadsurenone