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

Research output: Contribution to journalArticle

71 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Midazolam
Metabolism
Liver
Erythromycin
Physiological models
Itraconazole
Cimetidine
Plasmas
Oral Administration
Enzyme inhibition
Cytochrome P-450 CYP3A Inhibitors
In Vitro Techniques
Cytochrome P-450 CYP3A
Pharmacokinetics
Liver Microsomes
Enzyme Inhibitors
Enzymes
Kinetic parameters
Intravenous Administration
Rats

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Yamano, K., Yamamoto, K., Katashima, M., Kotaki, H., Takedomi, S., Matsuo, H., ... 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.

Prediction of midazolam - CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data. / Yamano, Katsuhiro; Yamamoto, Koujirou; Katashima, Masataka; Kotaki, Hajime; Takedomi, Sayuri; Matsuo, Hirotami; Ohtani, Hisakazu; Sawada, Yasufumi; Iga, Tatsuji.

In: Drug Metabolism and Disposition, Vol. 29, No. 4 I, 2001, p. 443-452.

Research output: Contribution to journalArticle

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, vol. 29, no. 4 I, pp. 443-452.
Yamano, Katsuhiro ; Yamamoto, Koujirou ; Katashima, Masataka ; Kotaki, Hajime ; Takedomi, Sayuri ; Matsuo, Hirotami ; Ohtani, Hisakazu ; Sawada, Yasufumi ; Iga, Tatsuji. / Prediction of midazolam - CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data. In: Drug Metabolism and Disposition. 2001 ; Vol. 29, No. 4 I. pp. 443-452.
@article{2624569d0bb440d3a3594b3c43aeae6f,
title = "Prediction of midazolam - CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data",
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.",
author = "Katsuhiro Yamano and Koujirou Yamamoto and Masataka Katashima and Hajime Kotaki and Sayuri Takedomi and Hirotami Matsuo and Hisakazu Ohtani and Yasufumi Sawada and Tatsuji Iga",
year = "2001",
language = "English",
volume = "29",
pages = "443--452",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "4 I",

}

TY - JOUR

T1 - Prediction of midazolam - CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data

AU - Yamano, Katsuhiro

AU - Yamamoto, Koujirou

AU - Katashima, Masataka

AU - Kotaki, Hajime

AU - Takedomi, Sayuri

AU - Matsuo, Hirotami

AU - Ohtani, Hisakazu

AU - Sawada, Yasufumi

AU - Iga, Tatsuji

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0035064595&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035064595&partnerID=8YFLogxK

M3 - Article

VL - 29

SP - 443

EP - 452

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 4 I

ER -