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In Vitro Evaluation of Hepatic and Extra-hepatic Metabolism of Coumarins Using Rat Subcellular Fractions: Correlation of In Vitro Clearance with In Vivo Data
| Content Provider | Scilit |
|---|---|
| Author | Behera, D. Damre, A. Varghese, A. Addepalli, V. |
| Copyright Year | 2008 |
| Abstract | 7-Ethoxycoumarin (7-EC) and 7-hydroxycoumarin (7-HC) were chosen as model compounds to study hepatic and extra-hepatic metabolism in rat tissue subcellular (microsomal and S9) fractions and to scale the observed in vitro clearance to in vivo plasma clearance. 7-EC and 7-HC showed significant metabolic degradation in liver subcellular fractions as compared to subcellular fractions obtained from intestine, kidney, lung and brain. The total in vitro metabolic clearance for 7-EC and 7-HC was determined by adding the individual in vitro organ clearance values obtained in hepatic and extra-hepatic microsomes or S9 fractions. The predicted in vivo clearance for 7-HC was 63.6 and 81.6 ml/min/kg by in vitro scaling from microsomes and S9 fractions, respectively. For 7-EC, the values were 78.5 and 76.8 ml/min/kg, respectively. The predicted clearance was found to be reasonably accurate with slight over- and underprediction. Interestingly, the relative contribution of hepatic and extra-hepatic metabolism to the total clearance of 7-EC and 7-HC was remarkably high, ranging from 62-77% and 22-38%, respectively, of the total metabolic clearance. It is concluded that the model of multi-organ subcellular fractions is a useful in vitro tool for the prediction of in vivo metabolic clearance, as it can provide information about the relative contribution of extra-hepatic and hepatic metabolism to total metabolic clearance. |
| Related Links | http://www.degruyter.com/downloadpdf/j/dmdi.2008.23.3-4/dmdi.2008.23.3-4.329/dmdi.2008.23.3-4.329.xml |
| Ending Page | 350 |
| Page Count | 22 |
| Starting Page | 329 |
| ISSN | 07925077 |
| e-ISSN | 21910162 |
| DOI | 10.1515/dmdi.2008.23.3-4.329 |
| Journal | Drug metabolism and drug interactions |
| Issue Number | 3-4 |
| Volume Number | 23 |
| Language | English |
| Publisher | Walter de Gruyter GmbH |
| Publisher Date | 2008-01-01 |
| Access Restriction | Open |
| Subject Keyword | Drug Metabolism and Drug Interactions Toxicology Model Extra Hepatic Subcellular Fractions Vitro Metabolic Clearance Journal: Drug metabolism and drug interactions, Issue- 2 |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology, Toxicology and Pharmaceutics Pharmacology (medical) |
