Hepatobiliary excretion and enterohepatic circulation of colchicine in rats
| Autor: | Shiou Mei Huang, Tung Hu Tsai, Chia Yuan Liu, Yu-Jen Chen, Pen Ho Yeh |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Diarrhea
Male Microdialysis medicine.medical_specialty Pharmaceutical Science Pharmacology Excretion Rats Sprague-Dawley chemistry.chemical_compound Pharmacokinetics Cyclosporin a Internal medicine Enterohepatic Circulation Weight Loss medicine Colchicine Animals Bile Enterohepatic circulation Dose-Response Relationship Drug Rats Proadifen Endocrinology chemistry Liver Toxicity Cyclosporine |
| Zdroj: | International journal of pharmaceutics. 350(1-2) |
| ISSN: | 0378-5173 |
| Popis: | This study investigated the pharmacokinetics of unbound colchicine in rat blood, liver and bile, and its interaction with cyclosporin A (CsA; P-glycoprotein inhibitor) and proadifen (non-specific cytochrome P450 inhibitor) by using a microdialysis and liquid chromatographic system. The pharmacokinetics of colchicine in rat blood showed elimination in a nonlinear manner within the dosage ranges of 1–10 mg/kg. Twenty minutes after administration, colchicine reached maximum concentration in the liver and bile. The liver-to-blood distribution ratios (AUC liver /AUC blood ) were 1.8 ± 0.6, 1.0 ± 0.2 and 0.8 ± 0.1, and the bile-to-blood distribution ratios (AUC bile /AUC blood ) were 121.6 ± 24.7, 102.2 ± 13.4 and 116.5 ± 18.4 at dosages of 1, 3 and 10 mg/kg, respectively. The high hepatobiliary excretion of colchicine may lead to increased toxicity in normal tissues and indicates that colchicine undergoes hepatobiliary excretion against the concentration gradient from bile-to-blood. The area under the curse (AUC) of colchicine in the liver increased in the proadifen-treated groups, suggesting that metabolism of colchicine may involve cytochrome P450. CsA pretreatment caused an increase in the AUC of colchicine in the blood, a decreased AUC in the bile, and a profound decline in the bile-to-blood distribution ratio. Furthermore, the acute diarrhea and body weight loss caused by colchicine were delayed by pretreatment with CsA. These results indicate that the hepatobiliary excretion of colchicine was regulated by P-glycoprotein (P-gp) and the related acute diarrhea could be modulated by CsA. By using a paired rats model, the enterohepatic circulation of colchicine was also observed. |
| Databáze: | OpenAIRE |
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