Prediction of theophylline clearance in CCl4-treated rats using in vivo CYP1A2 and CYP3A2 contents assessed with the PKCYP test.

Noriko Kose, Keiko Yamamoto, Yoshimichi Sai, Minae Isawa, Toshio Suwa, Emi Nakashima

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

We previously established a method to predict the drug metabolism capacity of injured liver based on pharmacokinetic estimation of the amount of cytochrome P450 (CYP) in vivo (PKCYP test), by introducing the apparent liver-to-blood free concentration gradient in vivo (qg) as a parameter. Here we show that the amount of CYP3A2 in CCl(4)-treated rats can be estimated appropriately by applying the PKCYP test using midazolam (MDZ) as a probe, assuming that the qg value in control rats does not change. We applied the results to predict the clearance of theophylline as a model drug with a physiologically based pharmacokinetic model. Male Sprague-Dawley rats were pretreated with CCl4, and the amount of CYP (A-CYP(vivo)) was quantified by Western blotting. The qg value of MDZ was determined in control rats and used to estimate the amounts of CYP3A2 in CCl4-treated rats; the result agreed well with the observed values. The qg value of CYP3A2 estimated with MDZ as a probe was used together with our previously reported value for CYP1A2 (theophylline metabolism in the liver is known to be almost entirely mediated by CYP3A2 and CYP1A2) to predict the total body clearance (CL(tot)) of theophylline in CCl4-treated rats. The predicted CL(tot) was about one-third of the observed value, which was considered acceptable. The time-course of theophylline concentration in serum simulated with a physiologically-based pharmacokinetic model agreed well with the observed values. Thus, the PKCYP test using MDZ as a probe can be used to predict the amount of CYP3A2 and the CL(tot) of theophylline in CCl4-treated rats.

Original languageEnglish
Pages (from-to)168-176
Number of pages9
JournalDrug Metabolism and Pharmacokinetics
Volume20
Issue number3
Publication statusPublished - 2005

Fingerprint

Cytochrome P-450 CYP1A2
Theophylline
Midazolam
Cytochrome P-450 Enzyme System
Pharmacokinetics
Liver
Pharmaceutical Preparations
Sprague Dawley Rats
Western Blotting
Serum

Cite this

Prediction of theophylline clearance in CCl4-treated rats using in vivo CYP1A2 and CYP3A2 contents assessed with the PKCYP test. / Kose, Noriko; Yamamoto, Keiko; Sai, Yoshimichi; Isawa, Minae; Suwa, Toshio; Nakashima, Emi.

In: Drug Metabolism and Pharmacokinetics, Vol. 20, No. 3, 2005, p. 168-176.

Research output: Contribution to journalArticle

Kose, Noriko ; Yamamoto, Keiko ; Sai, Yoshimichi ; Isawa, Minae ; Suwa, Toshio ; Nakashima, Emi. / Prediction of theophylline clearance in CCl4-treated rats using in vivo CYP1A2 and CYP3A2 contents assessed with the PKCYP test. In: Drug Metabolism and Pharmacokinetics. 2005 ; Vol. 20, No. 3. pp. 168-176.
@article{ef0056b8ca5a491b9d1bd9408e7e5d3f,
title = "Prediction of theophylline clearance in CCl4-treated rats using in vivo CYP1A2 and CYP3A2 contents assessed with the PKCYP test.",
abstract = "We previously established a method to predict the drug metabolism capacity of injured liver based on pharmacokinetic estimation of the amount of cytochrome P450 (CYP) in vivo (PKCYP test), by introducing the apparent liver-to-blood free concentration gradient in vivo (qg) as a parameter. Here we show that the amount of CYP3A2 in CCl(4)-treated rats can be estimated appropriately by applying the PKCYP test using midazolam (MDZ) as a probe, assuming that the qg value in control rats does not change. We applied the results to predict the clearance of theophylline as a model drug with a physiologically based pharmacokinetic model. Male Sprague-Dawley rats were pretreated with CCl4, and the amount of CYP (A-CYP(vivo)) was quantified by Western blotting. The qg value of MDZ was determined in control rats and used to estimate the amounts of CYP3A2 in CCl4-treated rats; the result agreed well with the observed values. The qg value of CYP3A2 estimated with MDZ as a probe was used together with our previously reported value for CYP1A2 (theophylline metabolism in the liver is known to be almost entirely mediated by CYP3A2 and CYP1A2) to predict the total body clearance (CL(tot)) of theophylline in CCl4-treated rats. The predicted CL(tot) was about one-third of the observed value, which was considered acceptable. The time-course of theophylline concentration in serum simulated with a physiologically-based pharmacokinetic model agreed well with the observed values. Thus, the PKCYP test using MDZ as a probe can be used to predict the amount of CYP3A2 and the CL(tot) of theophylline in CCl4-treated rats.",
author = "Noriko Kose and Keiko Yamamoto and Yoshimichi Sai and Minae Isawa and Toshio Suwa and Emi Nakashima",
year = "2005",
language = "English",
volume = "20",
pages = "168--176",
journal = "Drug Metabolism and Pharmacokinetics",
issn = "1347-4367",
publisher = "Japanese Society for the Study of Xenobiotics",
number = "3",

}

TY - JOUR

T1 - Prediction of theophylline clearance in CCl4-treated rats using in vivo CYP1A2 and CYP3A2 contents assessed with the PKCYP test.

AU - Kose, Noriko

AU - Yamamoto, Keiko

AU - Sai, Yoshimichi

AU - Isawa, Minae

AU - Suwa, Toshio

AU - Nakashima, Emi

PY - 2005

Y1 - 2005

N2 - We previously established a method to predict the drug metabolism capacity of injured liver based on pharmacokinetic estimation of the amount of cytochrome P450 (CYP) in vivo (PKCYP test), by introducing the apparent liver-to-blood free concentration gradient in vivo (qg) as a parameter. Here we show that the amount of CYP3A2 in CCl(4)-treated rats can be estimated appropriately by applying the PKCYP test using midazolam (MDZ) as a probe, assuming that the qg value in control rats does not change. We applied the results to predict the clearance of theophylline as a model drug with a physiologically based pharmacokinetic model. Male Sprague-Dawley rats were pretreated with CCl4, and the amount of CYP (A-CYP(vivo)) was quantified by Western blotting. The qg value of MDZ was determined in control rats and used to estimate the amounts of CYP3A2 in CCl4-treated rats; the result agreed well with the observed values. The qg value of CYP3A2 estimated with MDZ as a probe was used together with our previously reported value for CYP1A2 (theophylline metabolism in the liver is known to be almost entirely mediated by CYP3A2 and CYP1A2) to predict the total body clearance (CL(tot)) of theophylline in CCl4-treated rats. The predicted CL(tot) was about one-third of the observed value, which was considered acceptable. The time-course of theophylline concentration in serum simulated with a physiologically-based pharmacokinetic model agreed well with the observed values. Thus, the PKCYP test using MDZ as a probe can be used to predict the amount of CYP3A2 and the CL(tot) of theophylline in CCl4-treated rats.

AB - We previously established a method to predict the drug metabolism capacity of injured liver based on pharmacokinetic estimation of the amount of cytochrome P450 (CYP) in vivo (PKCYP test), by introducing the apparent liver-to-blood free concentration gradient in vivo (qg) as a parameter. Here we show that the amount of CYP3A2 in CCl(4)-treated rats can be estimated appropriately by applying the PKCYP test using midazolam (MDZ) as a probe, assuming that the qg value in control rats does not change. We applied the results to predict the clearance of theophylline as a model drug with a physiologically based pharmacokinetic model. Male Sprague-Dawley rats were pretreated with CCl4, and the amount of CYP (A-CYP(vivo)) was quantified by Western blotting. The qg value of MDZ was determined in control rats and used to estimate the amounts of CYP3A2 in CCl4-treated rats; the result agreed well with the observed values. The qg value of CYP3A2 estimated with MDZ as a probe was used together with our previously reported value for CYP1A2 (theophylline metabolism in the liver is known to be almost entirely mediated by CYP3A2 and CYP1A2) to predict the total body clearance (CL(tot)) of theophylline in CCl4-treated rats. The predicted CL(tot) was about one-third of the observed value, which was considered acceptable. The time-course of theophylline concentration in serum simulated with a physiologically-based pharmacokinetic model agreed well with the observed values. Thus, the PKCYP test using MDZ as a probe can be used to predict the amount of CYP3A2 and the CL(tot) of theophylline in CCl4-treated rats.

UR - http://www.scopus.com/inward/record.url?scp=25644434377&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=25644434377&partnerID=8YFLogxK

M3 - Article

VL - 20

SP - 168

EP - 176

JO - Drug Metabolism and Pharmacokinetics

JF - Drug Metabolism and Pharmacokinetics

SN - 1347-4367

IS - 3

ER -