Application of the PKCYP-test in cases of altered CYP1A2 for multiple CYP systems in rat models of disease

Noriko Matsunaga, Kenji Hattori, Hisashi Iizasa, Junko Kizu, Akira Takanaka, Emi Nakashima

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Previously, we established a method to assess drug metabolism capacity based on a pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test) by introducing an apparent liver-to-blood free concentration gradient in vivo (qg). The qg values were determined as the ratio of in vivo-in vitro clearance. In this study, we examined the application of the PKCYP-test to the clearance of acetanilide and caffeine mediated by CYP1A2 using rat models in which the levels of CYP enzymes were reduced. Rats fed a choline-deficient diet (CD-fed) and aged rats were used as models for a low level of CYP in the liver. In both rat models, the contribution (fCYP) of CYP1A2 to the in vivo intrinsic clearance values (CLint) of acetanilide and caffeine metabolism was less than unity, suggesting that other metabolic pathways are involved in the CLint. The in vivo clearance for CYP1A2 was estimated by multiplying fCYP by CLint, then the value of qg was determined as the ratio of in vivo-in vitro clearance. We predicted the level of CYP1A2 in CD-fed and aged rats, based on the clearance of acetanilide mediated by CYP1A2, using the qg value of control rats. The clearance of caffeine mediated by CYP1A2 in CD-fed and aged rats, as estimated from the predicted level of CYP1A2, correlated with the observed values. In conclusion, we have demonstrated that the PKCYP-test can be applied to CYP1A2 for drugs metabolized by multiple CYP isozymes, and/or to models involving reduced CYP.

Original languageEnglish
Pages (from-to)1037-1043
Number of pages7
JournalBiological and Pharmaceutical Bulletin
Volume24
Issue number9
DOIs
Publication statusPublished - 2001

Fingerprint

Cytochrome P-450 CYP1A2
Cytochrome P-450 Enzyme System
Caffeine
Liver
Choline
Metabolic Networks and Pathways
Pharmaceutical Preparations
Isoenzymes
Pharmacokinetics
Diet

Keywords

  • Aged
  • Choline-deficient
  • CYP1A2
  • PKCYP-test
  • Probe

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Application of the PKCYP-test in cases of altered CYP1A2 for multiple CYP systems in rat models of disease. / Matsunaga, Noriko; Hattori, Kenji; Iizasa, Hisashi; Kizu, Junko; Takanaka, Akira; Nakashima, Emi.

In: Biological and Pharmaceutical Bulletin, Vol. 24, No. 9, 2001, p. 1037-1043.

Research output: Contribution to journalArticle

Matsunaga, Noriko ; Hattori, Kenji ; Iizasa, Hisashi ; Kizu, Junko ; Takanaka, Akira ; Nakashima, Emi. / Application of the PKCYP-test in cases of altered CYP1A2 for multiple CYP systems in rat models of disease. In: Biological and Pharmaceutical Bulletin. 2001 ; Vol. 24, No. 9. pp. 1037-1043.
@article{12687d5240604ef38a775baa5c3ad418,
title = "Application of the PKCYP-test in cases of altered CYP1A2 for multiple CYP systems in rat models of disease",
abstract = "Previously, we established a method to assess drug metabolism capacity based on a pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test) by introducing an apparent liver-to-blood free concentration gradient in vivo (qg). The qg values were determined as the ratio of in vivo-in vitro clearance. In this study, we examined the application of the PKCYP-test to the clearance of acetanilide and caffeine mediated by CYP1A2 using rat models in which the levels of CYP enzymes were reduced. Rats fed a choline-deficient diet (CD-fed) and aged rats were used as models for a low level of CYP in the liver. In both rat models, the contribution (fCYP) of CYP1A2 to the in vivo intrinsic clearance values (CLint) of acetanilide and caffeine metabolism was less than unity, suggesting that other metabolic pathways are involved in the CLint. The in vivo clearance for CYP1A2 was estimated by multiplying fCYP by CLint, then the value of qg was determined as the ratio of in vivo-in vitro clearance. We predicted the level of CYP1A2 in CD-fed and aged rats, based on the clearance of acetanilide mediated by CYP1A2, using the qg value of control rats. The clearance of caffeine mediated by CYP1A2 in CD-fed and aged rats, as estimated from the predicted level of CYP1A2, correlated with the observed values. In conclusion, we have demonstrated that the PKCYP-test can be applied to CYP1A2 for drugs metabolized by multiple CYP isozymes, and/or to models involving reduced CYP.",
keywords = "Aged, Choline-deficient, CYP1A2, PKCYP-test, Probe",
author = "Noriko Matsunaga and Kenji Hattori and Hisashi Iizasa and Junko Kizu and Akira Takanaka and Emi Nakashima",
year = "2001",
doi = "10.1248/bpb.24.1037",
language = "English",
volume = "24",
pages = "1037--1043",
journal = "Biological and Pharmaceutical Bulletin",
issn = "0918-6158",
publisher = "Pharmaceutical Society of Japan",
number = "9",

}

TY - JOUR

T1 - Application of the PKCYP-test in cases of altered CYP1A2 for multiple CYP systems in rat models of disease

AU - Matsunaga, Noriko

AU - Hattori, Kenji

AU - Iizasa, Hisashi

AU - Kizu, Junko

AU - Takanaka, Akira

AU - Nakashima, Emi

PY - 2001

Y1 - 2001

N2 - Previously, we established a method to assess drug metabolism capacity based on a pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test) by introducing an apparent liver-to-blood free concentration gradient in vivo (qg). The qg values were determined as the ratio of in vivo-in vitro clearance. In this study, we examined the application of the PKCYP-test to the clearance of acetanilide and caffeine mediated by CYP1A2 using rat models in which the levels of CYP enzymes were reduced. Rats fed a choline-deficient diet (CD-fed) and aged rats were used as models for a low level of CYP in the liver. In both rat models, the contribution (fCYP) of CYP1A2 to the in vivo intrinsic clearance values (CLint) of acetanilide and caffeine metabolism was less than unity, suggesting that other metabolic pathways are involved in the CLint. The in vivo clearance for CYP1A2 was estimated by multiplying fCYP by CLint, then the value of qg was determined as the ratio of in vivo-in vitro clearance. We predicted the level of CYP1A2 in CD-fed and aged rats, based on the clearance of acetanilide mediated by CYP1A2, using the qg value of control rats. The clearance of caffeine mediated by CYP1A2 in CD-fed and aged rats, as estimated from the predicted level of CYP1A2, correlated with the observed values. In conclusion, we have demonstrated that the PKCYP-test can be applied to CYP1A2 for drugs metabolized by multiple CYP isozymes, and/or to models involving reduced CYP.

AB - Previously, we established a method to assess drug metabolism capacity based on a pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test) by introducing an apparent liver-to-blood free concentration gradient in vivo (qg). The qg values were determined as the ratio of in vivo-in vitro clearance. In this study, we examined the application of the PKCYP-test to the clearance of acetanilide and caffeine mediated by CYP1A2 using rat models in which the levels of CYP enzymes were reduced. Rats fed a choline-deficient diet (CD-fed) and aged rats were used as models for a low level of CYP in the liver. In both rat models, the contribution (fCYP) of CYP1A2 to the in vivo intrinsic clearance values (CLint) of acetanilide and caffeine metabolism was less than unity, suggesting that other metabolic pathways are involved in the CLint. The in vivo clearance for CYP1A2 was estimated by multiplying fCYP by CLint, then the value of qg was determined as the ratio of in vivo-in vitro clearance. We predicted the level of CYP1A2 in CD-fed and aged rats, based on the clearance of acetanilide mediated by CYP1A2, using the qg value of control rats. The clearance of caffeine mediated by CYP1A2 in CD-fed and aged rats, as estimated from the predicted level of CYP1A2, correlated with the observed values. In conclusion, we have demonstrated that the PKCYP-test can be applied to CYP1A2 for drugs metabolized by multiple CYP isozymes, and/or to models involving reduced CYP.

KW - Aged

KW - Choline-deficient

KW - CYP1A2

KW - PKCYP-test

KW - Probe

UR - http://www.scopus.com/inward/record.url?scp=0034826672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034826672&partnerID=8YFLogxK

U2 - 10.1248/bpb.24.1037

DO - 10.1248/bpb.24.1037

M3 - Article

C2 - 11558565

AN - SCOPUS:0034826672

VL - 24

SP - 1037

EP - 1043

JO - Biological and Pharmaceutical Bulletin

JF - Biological and Pharmaceutical Bulletin

SN - 0918-6158

IS - 9

ER -