Abstract
To evaluate the degree of drug-drug interaction concerning metabolic inhibition in the liver quantitatively, we tried to predict the plasma concentration increasing ratio (R) of midazolam (MDZ) by erythromycin (EM), diltiazem (DLZ), or verapamil (VER) in rats. MDZ was administered through the portal vein at the steady state of plasma concentration of these inhibitors. The R values in the area under the plasma concentration curve of MDZ in the presence of EM, DLZ, and VER were 2.02, 1.64, and 1.30, respectively. The liver to plasma unbound concentration ratios of EM, DLZ, and VER at the steady state after infusion were 20.8, 1.02, and 3.01, respectively, suggesting concentrative uptake of EM and VER into the liver. The predicted R value in the presence of EM calculated by use of plasma unbound concentration was 1.03, whereas the value calculated with liver unbound concentration was 1.61, which was very close to the observed value. These findings indicated the need to consider the concentrative uptake of inhibitors into the liver for the quantitative prediction of metabolic inhibition. However, the predicted values in the presence of DLZ or VER calculated by use of liver unbound concentration were still underestimated. This result may be due to the metabolic inhibition by the metabolites of both inhibitors. Therefore, when predicting the degree of metabolic inhibition quantitatively, the inhibitory effect by coadministered drugs and the disposition of these metabolites in the liver must also be considered.
Footnotes
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Send reprint requests to: Katsuhiro Yamano, Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 1-6, Kashima 2-chome, Yodogawa-ku, Osaka 532-8514, Japan.
- Abbreviations:
- CYP
- cytochrome P450
- MDZ
- midazolam
- EM
- erythromycin
- DLZ
- diltiazem
- ITZ
- itraconazole
- KTZ
- ketoconazole
- VER
- verapamil
- AUC
- area under the plasma concentration curve
- R
- increasing ratio
- MI
- CYP Fe(II)-metabolic intermediate
- Received May 4, 1999.
- Accepted November 15, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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