Prediction of midazolam - CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data

Katsuhiro Yamano, Koujirou Yamamoto, Masataka Katashima, Hajime Kotaki, Sayuri Takedomi, Hirotami Matsuo, Hisakazu Ohtani, Yasufumi Sawada, Tatsuji Iga

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Abstract

The extent of decreases in apparent hepatic clearance and intrinsic hepatic clearance of midazolam (MDZ) after intravenous administration of MDZ with concomitant oral administration of cimetidine (CIM), itraconazole (ITZ), or erythromycin (EM) was predicted using plasma unbound concentrations and liver unbound concentrations of inhibitors. When MDZ was concomitantly administered with CIM, the observed increase in MDZ concentration was successfully predicted using inhibition constants assessed by human liver microsome and liver-to-plasma unbound concentration ratios in rats. However, the extent of interaction with ITZ or EM was still underestimated even taking into account the concentrative uptake of inhibitors into liver. We could predict the degree of "mechanism-based" inhibition by EM on the hepatic metabolism of MDZ, after repeated administration of EM, by a physiological model incorporating the amount of active enzyme as well as the concentration of inhibitor. The maximum inactivation rate constant and the apparent inactivation constant of EM on MDZ metabolism were 0.0665 min-1 and 81.8 μM, respectively. These kinetic parameters for the inactivation of the enzyme were applied to the physiological model with pharmacokinetic parameters of EM and MDZ obtained from published results. Consequently, we estimated that cytochrome P450 3A4 in the liver after repeated oral administration of EM was inactivated, resulting in 2.6-fold increase in the plasma concentration of MDZ. The estimated extent of increase in MDZ concentration in our study correlated well with the observed value based on metabolic inhibition by EM from published results.

Original languageEnglish
Pages (from-to)443-452
Number of pages10
JournalDrug Metabolism and Disposition
Volume29
Issue number4 I
Publication statusPublished - 2001 Apr 18
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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    Yamano, K., Yamamoto, K., Katashima, M., Kotaki, H., Takedomi, S., Matsuo, H., Ohtani, H., Sawada, Y., & Iga, T. (2001). Prediction of midazolam - CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data. Drug Metabolism and Disposition, 29(4 I), 443-452.