Abstract
The contribution of the lung to drug metabolism was investigated in rats and the possibility of prediction of in vivo metabolism from in vitro studies using rat pulmonary microsomes was assessed. Lidocaine, midazolam, or nifedipine was administered to rats at a dose of 10 mg/kg by the intra-arterial, intravenous, and intraportal routes. The pulmonary extraction ratios of lidocaine, midazolam, and nifedipine, calculated from the area under the time-plasma concentration curve (AUC) after the intra-arterial and intravenous administrations, were 39.0 ± 0.5, 18.3 ± 0.7, and 12.3 ± 0.3%, respectively. The hepatic extraction ratios of lidocaine, midazolam, and nifedipine, calculated from the AUC after the intraportal and intravenous administrations, were 68.0 ± 3.3, 52.6 ± 0.4, and 13.5 ± 0.2%, respectively. These results showed that both the liver and the lung contributed to the metabolism of these drugs. The above in vivo pulmonary extraction ratios correlated with the in vitro intrinsic clearance values, which were corrected with the protein unbound ratio in microsomes and plasma, suggesting that pulmonary extraction ratios can be predicted quantitatively from in vitro data. The pulmonary intrinsic clearance values of lidocaine, midazolam, and nifedipine in rat microsomes were lower than their hepatic intrinsic clearance, showing that there was an organ difference in metabolism between the liver and lung. Our results support the importance of the estimation of pulmonary metabolism to predict the total clearance more accurately.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.032227.
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ABBREVIATIONS:
- ke
- terminal elimination rate constant
- AUC
- area under the time-plasma concentration curve
- Clast
- last data point
- Elung
- pulmonary extraction
- Eliver
- hepatic extraction
- AUCi.a.
- area under the time-plasma concentration curve after intra-arterial administration
- AUCi.p.
- area under the time-plasma concentration curve after intra-portal administration
- AUCi.v.
- area under the time-plasma concentration curve after intravenous administration
- CLtot, observed
- observed total clearance
- CLtot, calculated
- calculated total clearance
- CLlung
- pulmonary clearance
- CLliver
- hepatic clearance
- Qlung
- pulmonary blood flow
- Qliver
- hepatic blood flow
- fu, microsome
- protein unbound ratio in microsomes
- fb
- protein unbound ratio in blood.
- Received January 13, 2010.
- Accepted April 6, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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