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

Citation
N. Matsunaga et al., Application of the PKCYP-test in cases of altered CYP1A2 for multiple CYP systems in rat models of disease, BIOL PHAR B, 24(9), 2001, pp. 1037-1043
Citations number
22
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOLOGICAL & PHARMACEUTICAL BULLETIN
ISSN journal
0918-6158 → ACNP
Volume
24
Issue
9
Year of publication
2001
Pages
1037 - 1043
Database
ISI
SICI code
0918-6158(200109)24:9<1037:AOTPIC>2.0.ZU;2-M
Abstract
Previously, we established a method to-assess drug metabolism capacity base d on a pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test) by introducing an apparent liver-to-blood free concent ration 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 CYP 1A2 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 (f(C YP)) of CYP1A2 to the in vivo intrinsic clearance values (CLint) of acetani lide and caffeine metabolism was less than unity, suggesting that other met abolic pathways are involved in the CLint. The in vivo clearance for CYP1A2 was estimated by multiplying f(CYP) by CLint, then the value of qg was det ermined 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 me diated by CYP1A2, using the qg value of control rats. The clearance of caff eine mediated by CYP1A2 in CD-fed and aged rats, as estimated from the pred icted level of CYP1A2, correlated with the observed values. In conclusion, we have demonstrated that the PKCYP-test can be applied to C YP1A2 for drugs metabolized by multiple CYP isozymes, and/or to models invo lving reduced CYP.